Heterocycle substituted aryloxyaniline derivatives and their use as MDR ligands

ABSTRACT

An aryloxyaniline derivative represented by the formula:                    
     wherein Ar 1  and Ar 2  are the same or different, and are each a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or a naphthyl group, provided that Ar 1  and Ar 2  are not both phenyl or both naphthyl and are not phenyl and naphthyl, R 1  is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group or a group of the formula: —NR 2 (R 3 ) (wherein R 2  and R 3  are the same or different, and are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, X 1  is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoromethyl group, a carbamoyl group or an aminosulfonyl group, Y 1  is a branched or unbranched alkylene group having 1 to 6 carbon atoms or a single bond; and pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.09/485,006, filed Feb. 1,2000, filed under 35 USC 371 based on PCT/JP98/03442, filed Aug. 3,1998 and now issued as U.S. Pat. No. 6,333,358and claims priority of Japanese Application No. 209123/1997, filed Aug.14, 1997.

TECHNICAL FIELD

The present invention relates to a medicine, and more particularlyrelates to a medicine having a high affinity for MDR.

BACKGROUND ART

Benzodiazepine (Bz) receptors are recently classified into 2 subtypes ofcentral benzodiazepine receptor (CBR) located on GABA_(A) receptor/ionchannel complex and mitochondrial DBI (diazepam binding inhibitor,Neuropharmacol., 30, 1425-1433 (1991)) receptor (BDR) located on thecentral nervous system (glial cells) or adrenal glands (Clin.Neuropharmacol., 16, 401-417 (1993)).

MDR agonists act indirectly on GABA_(A)/ion channel complex viaendogenous neurosteroids and cause an anti-anxiety action. Accordingly,they have a possibility to be usable for diseases (obsessive disorders,panic disorders) on which the previous Bzs do not have a satisfactorilytherapeutic effect, and to alleviate side-effects such as excessivesedation or psychic dependence caused by the Bzs. Furthermore, MDRligands act indirectly on GABA_(A) receptors, and therefore, have apossibility of use as therapeutical agents of sleeping disorders,epilepsy, dyskinesia accompanied by muscle rigidity, feeding disorders,circulation disorders, recognition and learning disability or drugdependence (Progress in Neurobiology, 38, 379-395, 1992, ibid., 49,73-97, 1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30,1435-1440, 1991). In addition, MDR ligands have a possibility of use astherapeutic agents of cancer (Biochimica et Biophysica Acta, 1241,453-470, 1995), lipid metabolism abnormality (Eur. J. Pharmacol., 294,601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996),cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstractsof the fifth international conference on AIDS, p. 458, 1989),Alzheimer's disease (Alzheimer Dis. Assoc. Disotd., 2, 331-336, 1988) orHuntington chorea (Brain Res., 248, 396-401, 1982).

Some phenoxyaniline derivatives are reported in WO9533715, JP 61040249and JP 57208295. However, they have a hydrogen atom or an alkyl group asthe substituent on the nitrogen atom of the aniline, but there are notreported the derivatives having a carbonyl group as the substituent.Furthermore, the use of the derivatives of the above-mentioned patent isanti-inflammatory agents based on the action to arakidonic acid series,anti-arteriosclerosis drugs based on an increase of PGI₂ production, orheat sensitive recording materials, but there is not described affinityfor MDR and anti-anxiety based on affinity for MDR.

An object of the present invention is to provide pharmaceuticalcompounds which are effective on diseases on which the previous Bzs donot have a satisfactorily therapeutic effect, and have a high affinityfor MDR, and therefore, have a therapeutic or preventive effect on thecentral diseases such as anxiety, related diseases thereto, depression,epilepsy, etc. without side-effects such as excessive sedation orpsychic dependence caused by the Bzs. Furthermore, another object of thepresent invention is to provide therapeutic agents of sleepingdisorders, dyskinesia accompanied by muscle rigidity, feeding disorders,circulation disorders, recognition and learning disability, drugdependence, cancer, lipid metabolism abnormality, schizophrenia,cerebral infarction, AIDS, Alzheimer's disease or Huntington chorea.

DISCLOSURE OF THE INVENTION

As a result of extensive researches about aryloxyaniline derivatives,the present inventors have found novel aryloxyaniline derivatives havinga high affinity for MDR, thus the present invention has beenaccomplished.

The present invention is illustrated as follows: the present inventionis directed to an aryloxyaniline derivative represented by Formula [I]:

wherein Ar¹ and Ar² are the same or different, and are each asubstituted or unsubstituted phenyl group, a substituted orunsubstituted pyridyl group or naphthyl group, R¹ is a hydrogen atom, asubstituted or unsubstituted alkyl group having 1 to 10 carbon atoms, analkoxy group having 1 to 10 carbon atoms, a substituted or unsubstitutedphenyl group or a group of the formula: —NR²(R³) (wherein R² and R³ arethe same or different, and are each a hydrogen atom or an alkyl grouphaving 1 to 10 carbon atoms, or R² and R³ taken together with thenitrogen atom to which they are attached form a 4 to 10 membered cyclicamino group), X¹ is a hydrogen atom, an alkyl group having 1 to 5 carbonatoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, ahalogen atom, a trifluoro-methyl group, a carbamoyl group or anaminosulfonyl group, y¹ is a branched or unbranched alkylene grouphaving 1 to 6 carbon atoms or a single bond; or a pharmaceuticallyacceptable salt thereof.

In the present invention, the substituted phenyl group is a phenyl groupsubstituted with one to three members selected from the group consistingof an alkyl group having 1 to 10 carbon atoms, an alkyl group having 1to 10 carbon atoms substituted with halogen atoms; hydroxyl groups;alkanoyloxy groups having 1 to 10 carbon atoms; carboxyl groups oralkoxycarbonyl groups, an alkenyl group having 2 to 10 carbon atoms, analkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to10 carbon atoms, a group of the formula: —O—Z—R⁴ (wherein Z is abranched or unbranched alkylene group having 1 to 10 carbon atoms, andR⁴ is an amino group, an amino group substituted with one or two of analkyl group having 1 to 7 carbon atoms, a cyclic amino group having 2 to7 carbon atoms, a hydroxyl group, a carboxyl group or an alkoxycarbonylgroup), an alkanoyl group having 2 to 10 carbon atoms or a ketal formthereof, a formyl group or an acetal form thereof, a carboxyl group, analkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, acarbamoyl group substituted with one or two of an alkyl group having 1to 10 carbon atoms on the nitrogen atom, an aminosulfonyl group, anaminosulfonyl group substituted with one or two of an alkyl group having1 to 10 carbon atoms on the nitrogen atom, a halogen atom and a nitrogroup, and examples thereof are a 2-methylphenyl group, a 2-propylphenylgroup, a 2-isopropylphenyl group, a 2-cyclopentylphenyl group, a2-(1-hydroxyethyl)phenyl group, a 2-carboxymethylphenyl group, a2-methoxycarbonyl-phenyl group, a 2-vinylphenyl group, a 2-methoxyphenylgroup, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a2-ethoxyphenyl group, a 2-hexyloxyphenyl group, a 2-isopropoxyphenylgroup, a 2-cyclopentoxyphenyl group, a 2,5-dimethoxyphenyl group, a2,4,6-trimethoxyphenyl group, a 4-methylthiophenyl group, a2-isopropylthiophenyl group, a 4-cyclohexylthiophenyl group, a2-(2-dimethylamino-ethoxy)phenyl group, a 2-(2-hydroxyethoxy)phenylgroup, a 2-carboxymethoxyphenyl group, a 2-methoxycarbonylmethoxyphenylgroup, a 2-acetylphenyl group, a 2-(2-methyl-1,3-dioxolan-2-yl)phenylgroup, a 2-formylphenyl group, a 2-(1,3-dioxolan-2-yl)phenyl group, a2-carboxylphenyl group, a 2-(N-methylaminocarbonyl)phenyl group, a2-(N,N-dimethylamino-carbonyl)phenyl group, a 2-aminocarbonylphenylgroup, a 2-aminosulfonylphenyl group, a 4-aminosulfonylphenyl group, a2-methylaminosulfonylphenyl group, a 2-dimethylamino-sulfonylphenylgroup, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenylgroup, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenylgroup, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenylgroup, a 2,4-difluorophenyl group, a 2-nitrophenyl group, a2-aminophenyl group, a 2-pyrrolidinophenyl group and a4-dimethylaminophenyl group. The substituted pyridyl group refers to apyridyl group substituted with a straight or branched alkoxy grouphaving 1 to 10 carbon atoms, and examples thereof are a2-methoxy-3-pyridyl group, a 3-methoxy-2-pyridyl group and a4-methoxy-3-pyridyl group. The alkyl group having 1 to 10 carbon atomsrefers to a straight, branched or cyclic alkyl group, and examplesthereof are a methyl group, an ethyl group, a propyl group, an isopropylgroup, a cyclopropyl group, a butyl group, an isobutyl group, acyclobutyl group, a cyclopropylmethyl group, a pentyl group, anisopentyl group, a cyclopentyl group, a cyclobutylmethyl group, a1-ethylpropyl group, a hexyl group, an isohexyl group, a cyclohexylgroup, a cyclopentylmethyl group, a 1-ethylbutyl group, a heptyl group,an isoheptyl group, a cyclohexylmethyl group, an octyl group, a nonylgroup and a decyl group. The substituted alkyl group having 1 to 10carbon atoms refers to an alkyl group substituted with a hydroxyl group,an alkanoyloxy group, an alkanoyl group, an alkoxy group, a halogenatom, an azido group, an amino group or a carboxyl group, and examplesthereof are a hydroxymethyl group, an acetyloxymethyl group, amethoxymethyl group, a chloromethyl group, a trifluoromethyl group, anazidomethyl group, an aminomethyl group, a dimethylaminomethyl group anda pyrrolidinomethyl group. The alkoxy group having 1 to 10 carbon atomsrefers to a straight, branched or cyclic alkoxy group, and examplesthereof are a methoxy group, an ethoxy group, a propoxy group, anisopropoxy group, a butoxy group, an isobutoxy group, acyclopropylmethoxy group, a pentyloxy group, an isopentyloxy group, ahexyloxy group, a heptyloxy group, an octyloxy group, a nonyloxy groupand a decyloxy group. The alkyl group having 1 to 10 carbon atomsrepresented by R² and R³ refers to a straight, branched or cyclic alkylgroup, accordingly, when R² and R³ are each the alkyl group having 1 to10 carbon atoms, examples of the group of —NR²(R³) are a methylaminogroup, an ethylamino group, a propylamino group, an isopropylaminogroup, a butylamino group, an isobutylamino group, acyclopropyl-methylamino group, a pentylamino group, an isopentylaminogroup, a cyclopentylamino group, a cyclobutylmethylamino group, a1-ethylpropylamino group, a hexylamino group, an isohexylamino group, acyclohexylamino group, a cyclopentyl-methylamino group, a1-ethylbutylamino group, a heptylamino group, an isoheptylamino group, acyclohexylmethylamino group, an octylamino group, a nonylamino group, adecylamino group, a dimethylamino group, a diethylamino group, adipropylamino group, a dibutylamino group, a dipentylamino group, adihexylamino group, an N-methylethylamino group, an N-methylpropylaminogroup, an N-methylbutylamino group, an N-methylpentylamino group, anN-methylhexylamino group, an N-ethylpropylamino group, anN-ethylbutylamino group and an N-ethylpentylamino group. The 4 to 10membered cyclic amino group represented by the group of —NR²(R³) refersto a cyclic amino group which may optionally have a nitrogen atom or anoxygen atom, and examples thereof are a pyrrolidino group, a piperidinogroup, a piperazino group, an N-methylpiperazino group and a morpholinogroup. The alkyl group having 1 to 5 carbon atoms represented by X¹refers to a straight, branched or cyclic alkyl group, and examplesthereof are a methyl group, an ethyl group, a propyl group, an isopropylgroup, a cyclopropyl group, a butyl group, an isobutyl group, acyclobutyl group and a cyclopropylmethyl group. The alkoxy group having1 to 5 carbon atoms refers to a straight, branched or cyclic alkoxygroup, and examples thereof are a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group, a butoxy group, an isobutoxy groupand a cyclopropylmethoxy group. Examples of the branched or unbranchedalkylene group having 1 to 6 carbon atoms represented by Y¹ are amethylene group, an ethylene group, a propylene group, a methylmethylenegroup and a dimethylmethylene group. The halogen atom refers to afluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Examples of the pharmaceutically acceptable salt in the presentinvention are salts with mineral acids (e.g. sulfuric acid, hydrochloricacid or phosphoric acid), organic acids (e.g. acetic acid, oxalic acid,lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonicacid or benzenesulfonic acid), metal ions (e.g. a sodium ion, apotassium ion or a calcium ion), organic bases (e.g. diethanolamine) orammonium salt.

The compound of Formula [I] can be prepared by the following generalpreparation methods 1 to 6. In the following reaction formulae, Ar¹,Ar², R¹, X¹ and Y¹ are as defined above, y² is a single bond or analkylene group having 1 to 5 carbon atoms which is unsubstituted orsubstituted with an alkyl group having 1 to 3 carbon atoms, R⁵ is analkyl group having 1 to 3 carbon atoms or a hydrogen atom, X² is anacyloxy group having 1 to 10 carbon atoms, a chlorine atom, a bromineatom, a hydroxyl group or an alkoxy group having 1 to 5 carbon atoms, X³is a chlorine atom, a bromine atom or an iodine atom.

General Preparation Method 1

An aniline derivative (1) is reacted with a carbonyl derivative (2) inthe presence or absence of an acid catalyst in an inert solvent andsubjected to reduction, or a mixture of the aniline derivative (1) andthe carbonyl derivative (2) is subjected to reduction in the presence orabsence of an acid catalyst in an inert solvent to give a compound (3).The compound (3) is reacted with an N-carbonylating agent in thepresence or absence of a base in an inert solvent to give a compound (4)of the present invention. Alternatively, phosgene as the N-carbonylatingagent is reacted with the compound (3) to give a chlorocarbonylderivative, which is then reacted with an alcohol or an amine in thepresence or absence of a base, thereby the compound (4) of the presentinvention is also obtained.

Examples of the acid catalyst are a halogenated hydrogen (e.g. hydrogenchloride or hydrogen bromide), an inorganic acid (e.g. hydrochloric acidor sulfuric acid), an organic acid (e.g. acetic acid or tosylic acid),PPTS, piperidine hydrochloride, etc.

The reduction is carried out by using a borane reductant (e.g. sodiumborohydride, lithium borohydride or sodium cyanoborohydride), or analuminum reductant (e.g. lithium-aluminum hydride), or carried out byhydrogenation using a catalyst such as palladium, platinum dioxide orRaney nickel. Examples of the N-carbonylating agent are an acyl halide,an organic acid anhydride, an alkoxycarbonyl halide, a carbamoyl halide,cyanic acid (formed from potassium cyanate and acetic acid in thereaction solution) and an isocyanate. Examples of the base are anorganic amine (e.g. triethylamine, diisopropylethylamine or pyridine),and an inorganic base (e.g. potassium carbonate, sodium hydroxide,sodium hydride or a metallic sodium). Examples of the inert solvent arean alcohol (e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran),a hydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbonsolvent (e.g. chloroform or dichloromethane), acetonitrile, water and amixture thereof.

General Preparation Method 2

A compound (7), i.e. the compound (3) wherein R⁵ is a hydrogen atom, isalso obtained by reacting the aniline derivative (1) with a carboxylicanhydride, an acyl halide, a carboxylic acid or a carboxylic acid ester,each of which is represented by a compound (5), in the presence orabsence of a base in an inert solvent to give an amide compound (6), andthen reacting the amide compound (6) with a reductant in an inertsolvent.

General Preparation Method 3

The aniline derivative (1) is reacted with an N-carbonylating agent inthe presence or absence of a base in an inert solvent to give a compound(8), which is then reacted with a halogenated compound (9) in thepresence of a base, if necessary, by using a phase transfer catalyst, acopper powder or a cuprous halide in an inert solvent, thereby there isobtained a compound (10) of the present invention. Alternatively,phosgene as the N-carbonylating agent is reacted with the compound (1)to give a chlorocarbonyl derivative, which is then reacted with analcohol or an amine in the presence of a base, thereby there is alsoobtained the compound (8).

Examples of the N-carbonylating agent are an acyl halide, an organicacid anhydride, an alkoxycarbonyl halide, a carbamoyl halide, cyanicacid (formed from potassium cyanate and acetic acid in the reactionsolution) and an isocyanate. Examples of the base are an organic amine(e.g. triethylamine, diisopropylethylamine or pyridine), an inorganicbase (e.g. potassium carbonate, sodium hydroxide, sodium hydride ormetallic sodium) and an alcoholate (e.g. potassium t-butoxide or sodiumethoxide). Examples of the phase transfer catalyst are a quaternaryammonium salt (e.g. benzyltriethyl ammonium bromide) or a crown ether(e.g. 18-crown-6 ether). Examples of the inert solvent are an alcohol(e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), ahydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent(e.g. dichloromethane or chloroform), a ketone solvent (e.g. acetone),acetonitrile, N,N-dimethylformamide, nitrobenzene, water and a mixturethereof.

General Preparation Method 4

When one or both of Ar¹ and Ar² have nitro groups, the nitro groups canbe each converted into an amino group by a hydrogenation or a metalreduction. The amino group is reacted with a halogenated compound in thepresence of a base, if necessary, by using a phase transfer catalyst inan inert solvent to be converted into an amino group substituted with astraight, branched or cyclic alkyl group having 1 to 10 carbon atoms.

The hydrogenation is carried out by using a catalyst such as palladium,platinum dioxide or Raney nickel, and the metal reduction is carried outby using a metal or a metal salt such as tin, a stannous salt (e.g.stannous chloride), iron, a ferrous salt (e.g. ferrous chloride) or zincunder conventional acidic, basic or neutral conditions. Examples of thebase are an organic amine (e.g. triethylamine, diisopropylethylamine orpyridine), an inorganic base (e.g. potassium carbonate, sodiumhydroxide, sodium hydride or metallic sodium), and an alcoholate (e.g.potassium t-butoxide or sodium ethoxide). Examples of the phase transfercatalyst are a quaternary ammonium salt (e.g. benzyltriethyl ammoniumbromide) and a crown ether (e.g. 18-crown-6 ether). Examples of theinert solvent are an alcohol (e.g. methanol or ethanol), an ether (e.g.tetrahydrofuran), a hydrocarbon (e.g. toluene or benzene), a halogenatedhydrocarbon solvent (e.g. dichloromethane or chloroform), acetonitrile,N,N-dimethylformamide, water and a mixture thereof.

General Preparation Method 5

When one or both of Ar¹ and Ar² have acyloxy groups, the acyloxy groupscan be each converted into a hydroxyl group by hydrolysis under acidicor basic conditions. The hydroxyl group is reacted with a halogenatedcompound in the presence of a base, if necessary, by using a phasetransfer catalyst in an inert solvent to be converted into a straight orbranched alkoxy group having 1 to 10 carbon atoms, a straight orbranched alkoxy group having 1 to 10 carbon atoms which is substitutedwith a substituted or unsubstituted amino group, or an alkoxy grouphaving 1 to 10 carbon atoms which is substituted with a carboxyl groupor an alkoxycarbonyl group.

The acidic or basic conditions mean to use an inorganic acid (e.g.hydrochloric acid or sulfuric acid) or an inorganic base (e.g. sodiumhydroxide or potassium hydroxide) in a solvent such as an alcohol (e.g.methanol or ethanol), an ether (e.g. tetrahydrofuran or dioxane), aketone (e.g. acetone), acetonitrile, N,N-dimethylformamide, water or amixture thereof. Examples of the base are an organic amine (e.g.triethylamine, diisopropylethylamine or pyridine), an inorganic base(e.g. potassium carbonate, sodium hydroxide, sodium hydride or metallicsodium), and an alcoholate (e.g. potassium t-butoxide or sodiumethoxide). Examples of the phase transfer catalyst are a quaternaryammonium salt (e.g. benzyltriethyl ammonium bromide) and a crown ether(e.g. 18-crown-6 ether). Examples of the inert solvent are an alcohol(e.g. methanol or ethanol), an ether (e.g. tetrahydrofuran), ahydrocarbon (e.g. toluene or benzene), a halogenated hydrocarbon solvent(e.g. dichloromethane or chloroform), acetonitrile,N,N-dimethylformamide, water and a mixture thereof.

General Preparation Method 6

When one or both of Ar¹ and Ar² have alkoxycarbonyl groups, thealkoxycarbonyl groups are each converted under conventional hydrolysisconditions of an ester into a carboxyl group, which can be thenconverted into an alkoxy-carbonyl group having 1 to 10 carbon atoms byesterification, or into a primary or secondary alkylaminocarbonyl grouphaving 1 to 10 carbon atoms or an aminocarbonyl group by amidation.

The hydrolysis conditions mean a reaction of a base (e.g. sodiumhydroxide or potassium hydroxide or sodium carbonate) or an inorganicacid (e.g. hydrochloric acid or sulfuric acid) in an inert solvent suchas an alcohol (e.g. methanol or ethanol) or a ketone (e.g. acetone). Theesterification means a reaction of an alkyl compound which issubstituted with chlorine atoms, bromine atoms or iodine atoms, or adialkyl sulfate, together with an inorganic base (e.g. sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate or sodiumhydride), an alcoholate (e.g. sodium methoxide or potassium t-butoxide)or an organic base (e.g. triethylamine or diisopropylethyl-amine), or areaction of an alcohol with an acid (e.g. hydrogen chloride or sulfuricacid). The amidation is carried out by converting the carboxyl groupwith thionyl chloride or triphenylphosphine-carbon tetrachloride into anacid halide, and then by reacting the acid halide with a correspondingamine derivative, or carried out by a conventional amidation (e.g. amixed acid anhydride method or a dicyclohexylcarbodiimide method).

General Preparation Method 7

When one or both of Ar¹ and Ar² have formyl or acyl groups, carbonylgroups of the formyl or acyl groups are each reacted with a Wittigreagent to be converted into an alkenyl group, which is then convertedinto an alkyl group by reduction.

The Wittig reagent includes a triphenylalkyl-phosphonium halide havingan alkyl group having 1 to 9 carbon atoms or a diethylalkyl phosphonate,and it is used in an inert solvent such as an alcohol (e.g. methanol orethanol), an ether (e.g. tetrahydrofuran), a hydrocarbon (e.g. tolueneor benzene), a halogenated hydrocarbon (e.g. methylene chloride orchloroform), acetonitrile or N,N-dimethylformamide together with a basesuch as sodium hydride, potassium t-butoxide, sodium ethoxide or n-butyllithium, if necessary, further together with a phase transfer catalystsuch as a quaternary ammonium salt (e.g. benzyltriethyl ammoniumbromide) or a crown ether (e.g. 18-crown-6 ether). The reductionincludes hydrogenation which is carried out by using a catalyst such aspalladium, platinum dioxide or Raney nickel.

General Preparation Method 8

When one or both of Ar¹ and Ar² have formyl or acyl groups, carbonylgroups of the formyl or acyl groups are each reacted with a Grignardreagent to be converted into a sec- or tert-alcohol compound. Thesec-alcohol compound is oxidized with various oxidants to be convertedinto an acyl group.

The Grignard reagent includes an alkyl or alkenyl magnesium halidehaving 1 to 9 carbon atoms such as methyl magnesium bromide or ethylmagnesium bromide. The oxidant includes oxalyl chloride-dimethylsulfoxide (Swern Oxidation), a chromic oxidant, a metal oxidant such asmanganese dioxide.

For the use of the compounds of the present invention as medicines, thecompounds of the present invention are mixed with conventional additivessuch as a filler, a binder, a disintegrater, a pH regulator or asolubulizer to form tablets, pills, capsules, granules, powders,solutions, emulsions, suspensions or injections, all of which can beprepared by conventional techniques.

The compound of the present invention can be administered orally orparenterally in the amount of from 0.1 to 500 mg/day to an adult patientin a single dose or several divided doses. This dose can be varieddepending on the type of diseases, age, body weight or symptoms of eachpatient.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention is illustrated in more detail by showing thefollowing examples and experiments.

EXAMPLE 1 Synthesis of N-Acetyl-N-(2-isopropoxybenzyl)-2-phenoxyaniline

(1) To a solution of 1.64 g of 2-isopropoxybenzaldehyde in 10 ml ofmethanol was added 1.85 g of 2-aminodiphenyl ether, and then the mixturewas stirred at room temperature for 30 minutes and cooled on ice-water.To the cooled reaction solution was gradually added 1.50 g of sodiumborohydride, followed by stirring under ice-cooling for 30 minutes andthen at room temperature for 30 minutes. An aqueous acetic acid solution(1.5 ml of acetic acid—30 ml of water) was added dropwise to thereaction solution, followed by stirring at room temperature for 10minutes. After extraction with ethyl acetate, the extract was washedwith a saturated aqueous sodium bicarbonate solution and a saturatedaqueous sodium chloride solution and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the filtratewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate−hexane=1:25) togive 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.

(2) In 30 ml of tetrahydrofuran were dissolved 2.65 g ofN-(2-isopropoxybenzyl)-2-phenoxyaniline and 1.5 ml of triethylamine, andthen 0.8 ml of acetyl chloride was added dropwise to the solution withstirring, followed by stirring for 30 minutes. The reaction mixture waspoured to water and extracted with ethyl acetate, and the extract waswashed with 0.5 N hydrochloric acid, a saturated aqueous sodiumbicarbonate solution and then with a saturated aqueous sodium chloridesolution, successively, and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the filtrate was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate−hexane=1:4) to give 2.92 gof N-acetyl-N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 2 Synthesis of N-Acetyl-N-(2,4-dimethoxybenzyl)-2-phenoxyaniline

(1) In 60 ml of methanol were dissolved 3.70 g of 2-aminodiphenyl etherand 3.70 g of 2,4-dimethoxybenzaldehyde, and then 70 mg of platinumoxide was added, followed by stirring at room temperature under ahydrogen stream overnight. To the reaction mixture was added 30 ml ofchloroform for dissolving the precipitate, and the catalyst wasseparated by filtration. The filtrate was concentrated under reducedpressure, and the residue was recrystallized from methanol to give 5.06g of N-(2,4-dimethoxybenzyl)-2-phenoxyaniline.

(2) To a solution of 1.00 g of N-(2,4-dimethoxy-benzyl)-2-phenoxyanilinein 1.18 g of pyridine was added 0.76 g of acetic anhydride, followed bystirring at room temperature for a day. The reaction mixture was pouredinto water and extracted with ethyl acetate, and the extract was washedwith 0.5 N hydrochloric acid, a saturated aqueous sodium bicarbonatesolution and a saturated aqueous sodium chloride solution, successively,and dried over anhydrous sodium sulfate. After removal of the dryingagent by filtration, the solvent was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:3) to give 1.09 g ofN-acetyl-N-(2,4-dimethoxybenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 3 Synthesis of N-Acetyl-N-(2-chlorobenzyl)-2-phenoxyaniline

(1) To a solution of 28.5 g of 2-phenoxyaniline and 25.8 ml oftriethylamine in 250 ml of methylene chloride was added dropwise 11.5 mlof acetyl chloride under ice-cooling. After stirring at room temperaturefor 1.5 hours, the reaction mixture was concentrated under reducedpressure, and the residue was poured into water and extracted with ethylacetate. The extract was washed with 0.5 N hydrochloric acid, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate−hexane=1:4) togive 33.7 g of N-acetyl-2-phenoxyaniline.

(2) To a suspension of 400 mg of sodium hydride (60% in oil) in 30 ml ofdimethylformamide was added 2.00 g of N-acetyl-2-phenoxyaniline at roomtemperature, followed by stirring at room temperature for 30 minutes. Tothe solution was added dropwise 1.64 g of 2-chlorobenzyl chloride atroom temperature with stirring, followed by stirring for 30 minutes.After addition of ice-water, the reaction mixture was extracted withether. The extract was washed with 0.5 N hydrochloric acid, a saturatedaqueous sodium bicarbonate solution and a saturated aqueous sodiumchloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate−hexane=1:4) togive 2.92 g of N-acetyl-N-(2-chlorobenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 4 Synthesis ofN-Aminocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline

In 20 ml of acetic acid was dissolved 1.54 g ofN-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner asin Example 1(1), and then an aqueous potassium cyanate solution (1.23 gof potassium cyanate and 10 ml of water) was added dropwise to thesolution, followed by stirring at room temperature for 2.5 hours. Thereaction mixture was poured into water and extracted with ethyl acetate,and the extract was washed with a saturated aqueous sodium bicarbonatesolution and a saturated sodium chloride solution and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate−hexane=1:3) to give 1.69 g ofN-aminocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 5 Synthesis ofN-(2-Methoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline

To a solution of 751 mg of triphosgene in 14 ml of methylene chloridewas added dropwise a solution of 2.03 g ofN-(2-methoxylbenzyl)-2-phenoxyaniline and 1.03 g ofdiisopropylethylamine in 25 ml of methylene chloride with stirring,followed by stirring at room temperature for 5 minutes. Into thesolution was blown an excess amount of methylamine with stirring,followed by stirring at room temperature for 5 minutes. Afterconcentration under reduced pressure, the reaction mixture was pouredinto ethyl acetate, washed with 5% hydrochloric acid, a saturatedaqueous sodium bicarbonate solution and a saturated aqueous sodiumchloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure, and the precipitated crystalswere recrystallized from ethyl acetate to give 2.02 g ofN-(2-methoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 6 Synthesis ofN-(2,5-Dimethoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline

To a solution of 3.43 ml of acetic acid and 8.36 ml of triethylamine in90 ml of benzene was added 12.9 ml of diphenylphosphoryl azide, followedby reflux under heating for 2 hours. To the reaction solution was added2.01 g of N-(2,5-dimethoxybenzyl)-2-phenoxyaniline synthesized in thesame manner as in Example 2(1), followed by reflux under heating for 6hours. The reaction mixture was poured into water, and the organic phasewas separated, washed with 5% hydrochloric acid, a saturated aqueoussodium bicarbonate solution and a saturated aqueous sodium chloridesolution, successively, and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the solvent was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate−hexane=1:2) andrecrystallized from diethyl ether to give 1.20 g ofN-(2,5-dimethoxybenzyl)-N-(N-methylaminocarbonyl)-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 7 Synthesis ofN-(2-Methoxybenzyl)-N-methoxycarbonyl-2-phenoxyaniline

(1) To a solution of 775 mg of triphosgene in 14 ml of methylenechloride was added gradually dropwise a solution of 2.16 g ofN-(2-methoxybenzyl)-2-phenoxyaniline and 1.10 g of diisopropylethylaminein 25 ml of methylene chloride with stirring, followed by stirring atroom temperature for 15 minutes. The reaction mixture was concentratedunder reduced pressure, poured into ethyl acetate, washed with 5%hydrochloric acid, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution, successively, and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate−hexane=1:15) to give 2.57 g ofN-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline.

(2) To a solution of 226 mg of sodium methoxide in 5 ml oftetrahydrofuran was added dropwise a solution of 1.22 g ofN-chlorocarbonyl-N-(2-methoxybenzyl)-2-phenoxyaniline in 5 ml oftetrahydrofuran under ice-cooling with stirring, followed by stirring atroom temperature for 20 minutes. The reaction mixture was concentratedunder reduced pressure, poured into water and extracted with ethylacetate, and the extract was washed with 5% hydrochloric acid, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate−hexane=1:6) andrecrystallized from ethyl acetate to give 1.18 g ofN-(2-methoxybenzyl)-N-methoxycarbonyl-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 8 Synthesis ofN-Aminoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline

(1) A solution of 1.51 g ofN-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in thesame manner as in Example 1 and 770 mg of sodium azide in 10 ml ofdimethylformamide was stirred at room temperature overnight. Thereaction mixture was poured into water and extracted with ethyl acetate.The extract was washed with 5% hydrochloric acid, a saturated aqueoussodium bicarbonate solution and a saturated aqueous sodium chloridesolution, successively, and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the solvent was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate−hexane=1:4) to give 1.55 gof N-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.

(2) To a solution of 647 mg ofN-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline in 7 ml of methanolwas added 20 mg of platinum oxide, followed by stirring under a hydrogenatmosphere at room temperature overnight. The reaction mixture wasfiltered through Celite, and after concentration under reduced pressure,purified by silica gel column chromatography (eluent; ethylacetate−hexane=1:6) and recrystallized from ethyl acetate-isopropylether to give 0.24 g ofN-aminoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 9 Synthesis ofN-Hydroxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline

(1) In 10 ml of benzene were stirred 1.01 g ofN-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, 1.30 g of sodiumacetate and 170 mg of tetra-n-butyl ammonium bromide at 80° C. for 5hours. The reaction mixture was poured into ethyl acetate, washed withwater and a saturated aqueous sodium chloride solution, successively,and dried over anhydrous sodium sulfate. After removal of the dryingagent by filtration, the solvent was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:3) to give 1.03 g ofN-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.

(2) In 6 ml of methanol was dissolved 525 mg ofN-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, and then 537 mg ofpotassium carbonate was added, followed by stirring at 50° C. for 7hours. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with 5% hydrochloric acid, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate−hexane=1:3) andallowed to stand at room temperature to give 450 mg ofN-hydroxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as crystals.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 10 Synthesis ofN-Acetyl-N-(2-pyrrolidinobenzyl)-2-phenoxyaniline monohydrochloride

(1) In 80 ml of methanol was dissolved 8.00 g ofN-acetyl-N-(2-nitrobenzyl)-2-phenoxyaniline synthesized in the samemanner as in Example 3, and then 66 mg of platinum dioxide was added,followed by stirring under a hydrogen atmosphere at room temperatureovernight. To the reaction mixture was added 40 ml of chloroform fordissolving the precipitate, and the catalyst was removed by filtration.The filtrate was concentrated under reduced pressure, and the residuewas recrystallized from methanol to give 6.88 g ofN-acetyl-N-(2-aminobenzyl)-2-phenoxyaniline.

(2) In 10 ml of N,N-dimethylformamide were stirred 1.00 g ofN-acetyl-N-(2-aminobenzyl)-2-phenoxyaniline, 680 mg of1,4-dibromobutane, 1.03 g of potassium carbonate and 50 mg of potassiumiodide at 70° C. for 3 days. The reaction mixture was poured into waterand extracted with ethyl acetate, and the extract was washed with waterand a saturated aqueous sodium chloride solution, successively, anddried over anhydrous sodium sulfate. After removal of the drying agentby filtration, the solvent was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography (eluent;ethyl acetate−hexane=1:3). The resulting product was dissolved in 5 mlof ether, and after addition of 0.9 ml of 4 N hydrogen chloride-ethylacetate, the solution was concentrated and recrystallized from ethylacetate-ether to give 0.49 g ofN-acetyl-N-(2-pyrrolidinobenzyl)-2-phenoxyaniline monohydrochloride.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 11 Synthesis ofN-Acetyl-N-(2-carboxymethoxybenzyl)-2-phenoxyaniline

(1) In 30 ml of methanol were dissolved 1.74 g of 2-acetoxybenzaldehydeand 1.85 g of 2-phenoxyaniline, and after stirring at room temperaturefor an hour, 3.00 g of sodium borohydride was added, followed bystirring at the same temperature for 30 minutes. To the reactionsolution was added dropwise an aqueous acetic acid solution (3.0 ml ofacetic acid and 60 ml of water), and after stirring at room temperaturefor 10 minutes, the mixture was extracted with ethyl acetate. Theextract was washed with a saturated aqueous sodium bicarbonate solutionand a saturated aqueous sodium chloride solution, and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure. Asolution of the residue and 4 ml of triethylamine in 50 ml of methylenechloride was cooled to 0° C., and 2.00 ml of acetyl chloride was addeddropwise with stirring, followed by stirring at room temperature for 20minutes. The reaction mixture was poured into water and extracted withethyl acetate. The extract was washed with 0.5 N hydrochloric acid, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure to give a crudeN-acetyl-N-(2-acetyloxybenzyl)-2-phenoxyaniline.

This was dissolved in 40 ml of methanol, and 14 ml of 5% aqueouspotassium hydroxide solution was added, followed by stirring at roomtemperature for an hour. The reaction mixture was concentrated underreduced pressure, poured into water and extracted with ethyl acetate.The extract was washed with 5% hydrochloric acid, a saturated aqueoussodium bicarbonate solution and a saturated aqueous sodium chloridesolution, successively, and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the solvent was concentratedunder reduced pressure, and the residue was crystallized fromdiisopropyl ether to give 1.86 g ofN-acetyl-N-(2-hydroxybenzyl)-2-phenoxyaniline.

(2) To a solution of 666 mg ofN-acetyl-N-(2-hydroxybenzyl)-2-phenoxyaniline in 10 ml ofN,N-dimethylformamide was added 80 mg of 60% NaH/oil, followed bystirring at room temperature for 30 minutes. To this was added 0.3 ml ofmethyl bromoacetate, followed by stirring at room temperature for 30minutes. The reaction solution was poured into 0.5 N hydrochloric acidand extracted with ethyl acetate. The extract was washed with 0.5 Nhydrochloric acid, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution, successively, and dried overanhydrous sodium sulfate. After filtration, the filtrate wasconcentrated under reduced pressure to give a crudeN-acetyl-N-(2-methoxycarbonylmethoxybenzyl)-2-phenoxyaniline.

This was dissolved in 10 ml of methanol, and 5% aqueous potassiumhydroxide solution was added and stirred at room temperature for anhour. The reaction solution was made acidic with 2 N hydrochloric acidand extracted with ethyl acetate, and the extract was washed with asaturated aqueous sodium chloride solution and dried over anhydroussodium sulfate. After removal of the drying agent by filtration, thesolvent was concentrated under reduced pressure, and the residue wascrystallized from diisopropyl ether to give 745 mg ofN-acetyl-N-(2-carboxymethoxybenzyl)-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 12 Synthesis of N-Acetyl-N-(2-propylbenzyl)-2-phenoxyaniline

(1) In 40 ml of acetone was dissolved 2.81 g ofN-acetyl-N-[2-(1,3-dioxolan-2-yl)benzyl]-2-phenoxyaniline synthesized inthe same manner as in Example 3, and then 0.10 g of p-toluenesulfonicacid monohydrate was added, followed by stirring at room temperature for6 hours. To the reaction solution was added a saturated aqueous sodiumbicarbonate solution, the acetone was concentrated under reducedpressure, and the residue was extracted with ethyl acetate, washed witha saturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution and dried over anhydrous sodium sulfate. Afterremoval of the drying agent by filtration, the solvent was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate−hexane=1:3), dried andallowed to stand at room temperature to give 2.12 g ofN-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline as crystals.

(2) To a suspension of 4.34 g of ethyltriphenyl-phosphonium bromide in20 ml of tetrahydrofuran was added dropwise 6.63 ml of 1.63 M n-butyllithium/hexane solution under a nitrogen stream, while keeping thetemperature of the reaction solution at −15 to −10° C. The temperatureof the reaction solution was gradually raised to room temperature, andafter stirring at room temperature for 20 minutes, a solution of 1.01 gof N-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 10 ml oftetrahydrofuran was added dropwise, followed by further stirring for anhour. After addition of a saturated aqueous ammonium chloride solution,the reaction solution was extracted with ethyl acetate, and the extractwas washed with a saturated aqueous sodium chloride solution and driedover anhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure to give859 mg of N-acetyl-N-[2-(propen-1-yl)benzyl]-2-phenoxyaniline as an oilin a mixture of the geometrical isomers at a ratio of about 3:2.

(3) In 7 ml of ethanol was dissolved 757 mg ofN-acetyl-N-[2-(propen-1-yl)benzyl]-2-phenoxyaniline (a mixture of thegeometrical isomers at a ratio of about 3:2), and 15 mg of platinumoxide was added, followed by stirring under a hydrogen atmosphere atroom temperature for 3 hours. The catalyst in the reaction solution wasremoved by filtration, the solvent was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:4) to give 647 mg ofN-acetyl-N-(2-propylbenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 13 Synthesis of N-Acetyl-N-(2-acetylbenzyl)-2-phenoxyaniline

(1) To an ice-cooled solution of 5.25 ml of 1M methylmagnesiumchloride/tetrahydrofuran diluted with 15 ml of tetrahydrofuran was addeddropwise a solution of 1.20 g ofN-acetyl-N-(2-formylbenzyl)-2-phenoxyaniline in 7 ml of tetrahydrofuran,followed by stirring at room temperature for an hour. The reactionsolution was again cooled on ice, and after addition of a saturatedaqueous ammonium chloride solution, extracted with ethyl acetate, andthe extract was washed with a saturated aqueous sodium chloride solutionand dried over anhydrous sodium sulfate. After removal of the dryingagent by filtration, the solvent was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:1) to give 1.19 g ofN-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline as an oil.

(2) A solution of 0.22 ml of oxalyl chloride in 13.5 ml ofdichloromethane was cooled to −70° C. or below on dry-ice—acetone, and asolution of 0.24 ml of dimethyl sulfoxide in 0.9 ml of dichloromethanewas added dropwise, followed by stirring for 10 minutes. To this wasadded dropwise a solution of 0.48 g ofN-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline in 4.5 ml ofdichloromethane, and the temperature of the reaction solution wasgradually raised to −45° C., followed by stirring at the sametemperature for an hour. To the reaction solution was added dropwise1.34 ml of triethylamine at −40° C. or below, followed by stirring at 0°C. for 20 minutes. The reaction solution, after addition of a saturatedaqueous ammonium chloride solution, was extracted with ethyl acetate,and the extract was washed with a saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate. After removal of thedrying agent by filtration, the solvent was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:1) and recrystallizedfrom ethyl acetate−hexane to give 0.41 g ofN-acetyl-N-(2-acetylbenzyl)-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 14 Synthesis ofN-Acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline

(1) To a mixture of 23 ml of methanol and 3.6 ml of 2 N aqueouspotassium hydroxide solution was added 2.26 g ofN-acetyl-N-(2-methoxycarbonylbenzyl)-2-phenoxyaniline synthesized in thesame manner as in Example 2, followed by stirring at 60° C. for an hour.The reaction mixture was concentrated under reduced pressure, water wasadded to the residue, and the mixture was made acidic with 2 Nhydrochloric acid and extracted with ethyl acetate. The extract waswashed with a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate−hexane=1:1) to give 2.01 g ofN-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline as an oil.

(2) In a mixture of 10 ml of tetrahydrofuran and 0.1 ml ofhexamethylphosphoramide was dissolved 0.50 g ofN-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, and 0.2 ml of thionylchloride was added, followed by stirring at room temperature for 3hours. The reaction mixture was concentrated, the residue was dissolvedin 10 ml of tetrahydrofuran, and 2 ml of 50% aqueous dimethylaminesolution was added dropwise with stirring. The reaction mixture waspoured into water and extracted with ethyl acetate, and the extract waswashed with 1 N hydrochloric acid, a saturated aqueous sodiumbicarbonate solution and a saturated aqueous sodium chloride solution,successively, and dried over anhydrous sodium sulfate. After removal ofthe drying agent by filtration, the solvent was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:3) to give 0.49 g ofN-acetyl-N-(2-dimethylaminocarbonylbenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 15 Synthesis ofN-Acetyl-N-(2-ethoxycarbonylbenzyl)-2-phenoxyaniline

In 10 ml of N,N-dimethylformamide were stirred 0.50 g ofN-acetyl-N-(2-carboxybenzyl)-2-phenoxyaniline, 0.20 g of anhydrouspotassium carbonate and 0.22 ml of diethyl sulfate at room temperaturefor 3 hours. The reaction mixture was poured into water and extractedwith ethyl acetate, and the extract was washed with 1 N hydrochloricacid, a saturated aqueous sodium bicarbonate solution and a saturatedaqueous sodium chloride solution, successively, and dried over anhydroussodium sulfate. After removal of the drying agent by filtration, thesolvent was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (eluent; ethylacetate−hexane=1:7) to give 0.50 g ofN-acetyl-N-(2-ethoxycarbonylbenzyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 16 Synthesis of N-Acetyl-N-(2-methoxyphenyl)-2-phenoxyaniline

In 20 ml of nitrobenzene were refluxed 2.27 g ofN-acetyl-2-phenoxyaniline, 1.3 ml of 2-iodoanisole, 1.38 g of potassiumcarbonate, 133 mg of a copper powder and 200 mg of copper bromide underheating for 8 hours. The reaction solution was cooled to roomtemperature, and after addition of ethyl acetate, the insoluble matterwas removed by filtration. The filtrate was washed with 0.5 Nhydrochloric acid, a saturated aqueous sodium bicarbonate solution and asaturated aqueous sodium chloride solution, successively, and dried overanhydrous sodium sulfate. After removal of the drying agent byfiltration, the solvent was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate−hexane=1:4) to give 660 mg ofN-acetyl-N-(2-methoxyphenyl)-2-phenoxyaniline as an oil.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

EXAMPLE 17 Synthesis ofN-Acetyl-N-[2-(2-methoxyphenyl)ethyl]-2-phenoxyaniline

(1) In 30 ml of toluene were dissolved 4.98 g of 2-methoxyphenylaceticacid and 0.5 ml of N,N-dimethylformamide, and then 4 ml of thionylchloride was added.

To a solution of 4.98 g of 2-methoxyphenylacetic acid and 0.5 ml ofN,N-dimethylformamide in 30 ml of toluene was added 4 ml of thionylchloride, and after stirring at 70° C. for an hour, the mixture wasconcentrated under reduced pressure. The residue was dissolved in 20 mlof methylene chloride and added dropwise to an ice-cooled solution of5.55 g of 2-phenoxyaniline and 4.6 ml of triethylamine in 30 ml ofmethylene chloride with stirring, followed by stirring at roomtemperature for an hour. The reaction solution was concentrated underreduced pressure, and after addition of ice-water, extracted with ethylacetate, and the extract was washed with 0.5 N hydrochloric acid, asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, successively, and dried over anhydrous sodiumsulfate. After removal of the drying agent by filtration, the solventwas concentrated under reduced pressure.

The residue was dissolved in 40 ml of tetrahydrofuran and added dropwiseto a suspension of 1.70 g of aluminum lithium hydride in 40 ml oftetrahydrofuran, followed by reflux under heating for 30 minutes. Thereaction mixture was cooled with ice-water, and a saturated aqueoussodium sulfate solution was added dropwise with stirring. The insolublematter in the reaction solution was removed by filtration through ananhydrous magnesium sulfate plate, the filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (eluent; ethyl acetate−hexane=1:10) to give 8.23 g ofN-[2-(2-methoxyphenyl)ethyl]-2-phenoxyaniline as an oil.

(2) The same reaction and working-up as in Example 1(2) were carried outusing 3.19 g of N-[2-(2-methoxyphenyl)ethyl]-2-phenoxyaniline, andcrystallization from hexane gave 2.95 g ofN-acetyl-N-[2-(2-methoxyphenyl)ethyl]-2-phenoxyaniline.

The structures and physical property data of the present compound andthe compounds prepared similarly are shown in Tables 1 and 2.

TABLE 1

Comp. Exp. m.p. (Recry. Sol.*³) No.*¹ No.*² Ar¹—Y¹ Ar² R¹ X¹ (° C.) 0013 3-MeO—Ph—CH₂ Ph Me H oil*⁶ 002 3 4-MeO—Ph—CH₂ Ph Me H 99.5-100.0(Hex-Et₂O) 003 1 2-EtO—Ph—CH₂ Ph Me H oil*⁶ 004 3 2-EtO—Ph—CH₂ Ph Me4-Cl 103.5-104.0 (Hex) 005 1 2-n-PrO—Ph—CH₂ Ph Me H oil*⁶ 006 32-n-PrO—Ph—CH₂ Ph Me 4-Cl 95.5-96.0 (Hex) 007 1 2-i-PrO—Ph—CH₂ Ph Me Hoil*⁶ 008 3 2-i-PrO—Ph—CH₂ Ph Me 4-Cl 108.0-108.5 (Hex) 009 12-i-BuO—Ph—CH₂ Ph Me H oil*⁶ 010 1 2-n-PenO—Ph—CH₂ Ph Me H oil*⁶ 011 12-i-PenO—Ph—CH₂ Ph Me H oil*⁶ 012 17 2-MeO—Ph—(CH₂)₂ Ph Me H 79.0-80.0(Hex*⁶) 013 16 2-MeO—Ph Ph Me H oil*⁶ 014 2 2-MeO—Ph—CH(Me) Ph Me H96.5-97.0 (standing*⁴) 015 3 2,3-(MeO)₂—Ph—CH₂ Ph Me H oil*⁶ 016 22,4-(MeO)₂—Ph—CH₂ Ph Me H oil*⁶ 017 3 2,5-(MeO)₂—Ph—CH₂ Ph Me H oil*⁶018 3 2,5-(MeO)₂—Ph—CH₂ Ph Me 4-Me oil*⁶ 019 3 2,5-(MeO)₂—Ph—CH₂ Ph Me5-Me 108.0-109.0 (standing*⁴) 020 3 2,5-(MeO)₂—Ph—CH₂ Ph Me 4-F oil*⁶021 3 2,5-(MeO)₂—Ph—CH₂ Ph Me 5-F 92.5-93.5 (IPE) 022 32,5-(MeO)₂—Ph—CH₂ Ph Me 4-Cl 103.5-105.0 (IPE) 023 3 2,5-(MeO)₂—Ph—CH₂Ph Me 5-Cl 114.0-114.5 (IPE) 024 2 2,6-(MeO)₂—Ph—CH₂ Ph Me H oil*⁶ 025 33,5-(MeO)₂—Ph—CH₂ Ph Me H oil*⁶ 026 2 2,4,6-(MeO)₃—Ph—CH₂ Ph Me H122.0-123.0 (AcOEt-Hex) 027 11 2-HO—Ph—CH₂ Ph Me H 123.0-124.5 (IPE*⁵)028 11 2-MeCOO—Ph—CH₂ Ph Me H oil*⁶ 029 3 2-Cl—Ph—CH₂ Ph Me H oil*⁶ 0303 3-Cl—Ph—CH₂ Ph Me H oil*⁶ 031 3 4-Cl—Ph—CH₂ Ph Me H 92.0-93.0(Hex-Et₂O) 032 3 2-F—Ph—CH₂ Ph Me H 90.0-90.5 (IPE) 033 3 2-Br—Ph—CH₂ PhMe H 84.0-84.5 (IPE) 034 3 2-MeS—Ph—CH₂ Ph Me H oil*⁶ 035 112-HO₂CCH₂O—Ph—CH₂ Ph Me H 156.5-157.0 (IPE*⁵) 036 112-HO₂CC(Me)₂O—Ph—CH₂ Ph Me H 65.0-67.0 (standing*⁴) 037 12-(Me₂N(CH₂)₂O)—Ph—CH₂ Ph Me H oil*⁶ 038 13 2-CH₃(HO)CH—Ph—CH₂ Ph Me Hoil*⁶ 039 13 2-Et(HO)CH—Ph—CH₂ Ph Me H oil*⁶ 040 2 2-MeO₂C—Ph—CH₂ Ph MeH 76.0-78.0 (IPE) 041 15 2-EtO₂C—Ph—CH₂ Ph Me H oil*⁶ 042 142-HO₂C—Ph—CH₂ Ph Me H oil*⁶ 043 14 2-MeNHCO—Ph—CH₂ Ph Me H oil*⁶ 044 142-Me₂NCO—Ph—CH₂ Ph Me H oil*⁶ 045 3 2-(—O(CH₂)₂O—)CH—Ph—CH₂ Ph Me Hoil*⁶ 046 12 2-OHC—Ph—CH₂ Ph Me H 114.0-117.0 (standing*⁴) 047 132-CH₃CO—Ph—CH₂ Ph Me H 110.0-110.5 (AcOEt-Hex) 048 13 2-EtCO—Ph—CH₂ PhMe H oil*⁶ 049 1 2-Me—Ph—CH₂ Ph Me H 83.5-84.0 (IPE) 050 122-n-Pr—Ph—CH₂ Ph Me H oil*⁶ 051 12 2-CH₂═CH—Ph—CH₂ Ph Me H oil*⁶ 052 12-NO₂—Ph—CH₂ Ph Me H 96.0-96.5 (AcOEt-Hex) 053 10 2-NH₂—Ph—CH₂ Ph Me H155.5-156.0 (MeOH) 054 10 2-pyrrolidino-Ph—CH₂ Ph Me H 110.0-112.5(AcOEt-Et₂O) 055 2 4-Me₂N—Ph—CH₂ Ph Me H oil*⁶ 056 3 Ph—CH₂ Ph Me H80.5-81.0 (Et₂O) 057 3 2-Py—CH₂ Ph Me H 86.5-87.5 (Et₂O) 058 3 3-Py—CH₂Ph Me H 83.5-84.0 (IPE) 059 3 4-Py—CH₂ Ph Me H 114.5-115.0 (Et₂O) 060 13-MeO-2-Py—CH₂ Ph Me H 95.0-96.0 (standing*⁴) 061 1 2-MeO-3-Py—CH₂ Ph MeH 78.5-79.0 (IPE-Hex) 062 1 4-MeO-3-Py—CH₂ Ph Me H 90.5-91.0(standing*⁴) 063 2 2-MeO—Ph—CH₂ 1-Naph Me H 66.0-68.0 (AcOEt-Hex) 064 32-MeO—Ph—CH₂ Ph Et H oil*⁶ 065 3 2-MeO—Ph—CH₂ Ph Et 4-Cl oil*⁶ 066 32-EtO—Ph—CH₂ Ph Et 4-Cl 81.5-83.0 (Hex) 067 3 2-n-PrO—Ph—CH₂ Ph Et 4-Cl87.5-88.0 (Hex) 068 3 2-i-PrO—Ph—CH₂ Ph Et 4-Cl oil*⁶ 069 32,5-(MeO)₂—Ph—CH₂ Ph Et 4-Cl oil*⁶ 070 2 2-MeO₂C—Ph—CH₂ Ph Et H oil*⁶071 1 2-MeO—Ph—CH₂ Ph n-Pr H oil*⁶ 072 1 2-MeO—Ph—CH₂ Ph i-Pr H94.5-95.0 (Et₂O) 073 1 2-MeO—Ph—CH₂ Ph n-Bu H oil*⁶ 074 1 2-MeO—Ph—CH₂Ph i-Bu H oil*⁶ 075 1 2-MeO—Ph—CH₂ Ph n-Pen H oil*⁶ 076 1 2-MeO—Ph—CH₂Ph c-Pr H 73.0-74.0 (Et₂O-Hex) 077 1 2-MeO—Ph—CH₂ Ph c-Bu H 85.0-86.0(Et₂O-Hex) 078 1 2-MeO—Ph—CH₂ Ph c-Pen H 92.5-93.5 (Et₂O-Hex) 079 12-MeO—Ph—CH₂ Ph Ph H 125.5-127.0 (AcOEt-Hex) 080 1 2-MeO—Ph—CH₂ Ph F₃C Hoil*⁶ 081 1 2-MeO—Ph—CH₂ Ph ClCH₂ H 83.0-83.5 (standing*⁴) 082 92-MeO—Ph—CH₂ Ph AcOCH₂ H oil*⁶ 083 8 2-MeO—Ph—CH₂ Ph N₃CH₂ H oil*⁶ 084 82-MeO—Ph—CH₂ Ph NH₂CH₂ H 85.0-86.0 (AcOEt-IPE) 085 9 2-MeO—Ph—CH₂ PhHOCH₂ H 70.0-71.0 (standing*⁴) 086 1 2-MeO—Ph—CH₂ Ph HO₂C(CH₂)₂ H136.5-138.5 (AcOEt-Hex) 087 3 2-MeO—Ph—CH₂ Ph H H oil*⁶ 088 32-EtO—Ph—CH₂ Ph H H oil*⁶ 089 4 2-MeO—Ph—CH₂ Ph NH₂ H 89.5-90.0 (AcOEt)090 5 2-MeO—Ph—CH₂ Ph NHMe H 133.0-134.0 (AcOEt) 091 5 2-EtO—Ph—CH₂ PhNHMe H 85.0-86.0 (AcOEt-IPE) 092 5 2-n-PrO—Ph—CH₂ Ph NHMe H 82.0-83.0(AcOEt-IPE) 093 5 2-i-PrO—Ph—CH₂ Ph NHMe H 99.0-99.5 (AcOEt-IPE) 094 62-n-PenO—Ph—CH₂ Ph NHMe H 82.5-83.5 (Et₂O) 095 6 2,5-(MeO)₂—Ph—CH₂ PhNHMe H 88.5-89.5 (Et₂O) 096 5 2-MeO₂C—Ph—CH₂ Ph NHMe H 107.0-108.0(standing*⁴) 097 5 2-MeO—Ph—CH₂ Ph NMe₂ H 94.5-95.0 (standing*⁴) 098 72-MeO—Ph—CH₂ Ph OMe H oil*⁶ 099 7 2-MeO—Ph—CH₂ Ph OEt H oil*⁶ 100 22-MeO—Ph—CH₂ 2-Me—Ph Me H oil*⁶ 101 2 2-MeO—Ph—CH₂ 3-Me—Ph Me H oil*⁶102 2 2-MeO—Ph—CH₂ 4-Me—Ph Me H 79.0-80.0 (AcOEt-Hex) 103 2 2-MeO—Ph—CH₂2-MeO—Ph Me H oil*⁶ 104 2 2-MeO—Ph—CH₂ 3-MeO—Ph Me H oil*⁶ 105 22-MeO—Ph—CH₂ 4-MeO—Ph Me H oil*⁶ 106 2 2-MeO—Ph—CH₂ 4-MeS—Ph Me H97.0-98.0 (Et₂O-Hex) 107 2 2-MeO—Ph—CH₂ 2-F—Ph Me H 104.0-105.0(AcOEt-Hex) 108 2 2-MeO—Ph—CH₂ 3-F—Ph Me H 54.0-55.0 (AcOEt-Hex) 109 22-MeO—Ph—CH₂ 4-F—Ph Me H oil*⁶ 110 2 2-MeO—Ph—CH₂ 4-Cl—Ph Me H 62.0-63.0(Et₂O-Hex) 111 2 2-MeO—Ph—CH₂ 4-Br—Ph Me H 116.0-117.0 (AcOEt-Hex) 112 22-MeO—Ph—CH₂ 2,4-F₂—Ph Me H 81.0-82.0 (Et₂O-Hex) 113 2 2-MeO—Ph—CH₂ 2-PyMe H 81.0-82.0 (Et₂O) 114 2 2-MeO—Ph—CH₂ 3-Py Me H 64.0-65.0 (AcOEt-Hex)115 2 2-MeO—Ph—CH₂ 4-Py Me H 93.0-94.0 (Et₂O) 116 3 2-MeO—Ph—CH₂ Ph Me4-F 83.0-84.0 (AcOEt-Hex) 117 3 2-MeO—Ph—CH₂ Ph Me 5-F 91.5-92.0(AcOEt-Hex) 118 3 2-MeO—Ph—CH₂ Ph Me 6-F oil*⁶ 119 3 2-MeO—Ph—CH₂ Ph Me3-Cl 105.5-106.5 (AcOEt-Hex) 120 3 2-MeO—Ph—CH₂ Ph Me 4-Cl 113.0-114.5(AcOEt-Hex) 121 3 2-MeO—Ph—CH₂ Ph Me 5-Cl 109.0-109.5 (AcOEt-Hex) 122 32-MeO—Ph—CH₂ Ph Me 3-Me 84.5-85.5 (AcOEt-Hex) 123 3 2-MeO—Ph—CH₂ Ph Me4-Me 107.5-108.0 (AcOEt-Hex) 124 3 2-MeO—Ph—CH₂ Ph Me 5-Me 81.5-82.0(AcOEt-Hex) 125 3 2-MeO—Ph—CH₂ Ph Me 5-CF 113.0-113.5 (AcOEt-Hex) 126 32-MeO—Ph—CH₂ Ph Me 5-MeO 125.5-126.0 (AcOEt-Hex) 127 3 2-MeO—Ph—CH₂ PhMe 4-PhO oil*⁶ 128 2 2-i-PrO—Ph—CH₂ 4-Me—Ph Me 4-Cl 95.0-96.0 (Et₂O-Hep)129 2 2-i-PrO—Ph—CH₂ 4-MeO—Ph Me 4-Cl 53.0-56.0 (Et₂O-Hep) 130 22-i-PrO—Ph—CH₂ 4-F—Ph Me 4-Cl 82.0-83.0 (Et₂O-Hep) 131 22,5-(MeO)₂—Ph—CH₂ 4-Me—Ph Me 4-Cl 109.0-110.0 (Et₂O-Hep) 132 22,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph Me 4-Cl 121.0-122.0 (Et₂O-Hep) 133 22,5-(MeO)₂—Ph—CH₂ 3-F—Ph Me 4-Cl 79.0-80.0 (Et₂O-Hep) 134 22,5-(MeO)₂—Ph—CH₂ 4-F—Ph Me 4-Cl 102.0-103.0 (Et₂O-Hep) 135 22,5-(MeO)₂—Ph—CH₂ 4-Me—Ph Me 5-Me 111.0-112.0 (Et₂O-Hex) 136 22,5-(MeO)₂—Ph—CH₂ 3-F—Ph Me 5-Me 98.0-99.0 (Et₂O-Hex) 137 22-i-PrO—Ph—CH₂ 4-F—Ph Et 5-Me 96.0-97.0 (Et₂O-Hex) 138 22,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph Et 5-Me 85.0-86.0 (Et₂O-Hex) 139 22,5-(MeO)₂—Ph—CH₂ 4-F—Ph Et 5-Me 79.0-80.0 (Et₂O-Hex) 140 52-i-PrO—Ph—CH₂ 3-F—Ph NHMe 5-Me 95.0-96.0 (Et₂O-Hex) 141 52-i-PrO—Ph—CH₂ 4-F—Ph NHMe 5-Me 96.0-97.0 (Et₂O-Hex) 142 52,5-(MeO)₂—Ph—CH₂ 4-Me—Ph NHMe 4-Cl 130.0-131.0 (Et₂O) 143 52,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph NHMe 4-Cl 153.0-154.0 (Et₂O) 144 52,5-(MeO)₂—Ph—CH₂ 3-F—Ph NHMe 4-Cl 133.0-134.0 (Et₂O) 145 52,5-(MeO)₂—Ph—CH₂ 4-F—Ph NHMe 4-Cl 127.0-128.0 (Et₂O) 146 52,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph NHMe 5-Me 119.0-120.0 (Et₂O-Hex) 147 52,5-(MeO)₂—Ph—CH₂ 3-F—Ph NHMe 5-Me 113.0-114.0 (Et₂O-Hex) 148 52,5-(MeO)₂—Ph—CH₂ 4-F—Ph NHMe 5-Me 99.0-100.0 (Et₂O-Hex) 149 22-MeO—Ph—CH₂ 3-Me₂N—Ph Me H 50.0-51.0 (Et₂O-Hex) 150 2 2-MeO—Ph—CH₂2-Me₂NCH₂—Ph Me H oil*⁶ 151 2 2-MeO—Ph—CH₂ 3-Me₂NCH₂—Ph Me H oil*⁶ 152 22-MeO—Ph—CH₂ 4-Me₂NCH₂—Ph Me H oil*⁶ 153 1 2-MeO—Ph—CH₂ 2-H₂NCO—Ph Me H199.0-200.0 (standing*⁴) 154 3 2-MeO—Ph—CH₂ 3-H₂NCO—Ph Me H 125.0-127.0(standing*⁴) 155 3 2-MeO—Ph—CH₂ 4-H₂NCO—Ph Me H 204.0-206.5 (standing*⁴)156 1 2-MeO—Ph—CH₂ 2-AcHNCO—Ph Me H 169.0-171.0 (standing*⁴) 157 32-MeO—Ph—CH₂ 4-H₂NSO₂—Ph Me H 78.0-79.0 (standing*⁴) 158 32,5-(MeO)₂—Ph—CH₂ 4-H₂NSO₂—Ph Me H 150.0-152.0 (standing*⁴) 159 12,5-(MeO)₂—Ph—CH₂ 2-H₂NCO—Ph Me H 184.5-185.5 (standing*⁴) 160 32,5-(MeO)₂—Ph—CH₂ 3-H₂NCO—Ph Me H oil*⁶ 161 3 2,5-(MeO)₂—Ph—CH₂4-H₂NCO—Ph Me H 178.0-180.0 (standing*⁴) 162 2 4-H₂NSO₂—Ph—CH₂ Ph Me H143.0-144.0 (EtOH-Et₂O) 163 2 2-H₂NSO₂—Ph—CH₂ Ph Me H 184.0-185.0 (EtOH)164 2 4-H₂NSO₂—Ph—CH₂ Ph Me 5-F 163.0-165.0 (EtOH) 165 2 2-H₂NSO₂—Ph—CH₂Ph Me 5-F 178.0-179.0 (EtOH) 166 2 2-HO-5-MeO—Ph—CH₂ Ph Me 5-F106.0-106.5 (standing*⁴) 167 2 2-i-PrO—Ph—CH₂ 3-F—Ph Me 4-Cl oil*⁶ 168 22-i-PrO—Ph—CH₂ 3-F—Ph Me 5-Me oil*⁶ 169 2 2-i-PrO—Ph—CH₂ 4-F—Ph Me 5-Meoil*⁶ 170 2 2-i-PrO—Ph—CH₂ 4-Me—Ph Me 5-Me oil*⁶ 171 2 2,5-(MeO)₂—Ph—CH₂4-F—Ph Me 5-Me oil*⁶ 172 2 2,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph Me 5-Me102.0-103.0 (AcOEt-Hex) 173 3 2-MeO—Ph—CH₂ Ph Me 5-H₂NCO 250.0-251.0(standing*⁴) 174 3 2,5-(MeO)₂—Ph—CH₂ Ph Me 5-H₂NCO 168.5-169.0(standing*⁴) 175 3 2-MeO—Ph—CH₂ Ph Me 5-H₂NSO₂ 192.5-193.5 (standing*⁴)176 3 2,5-(MeO)₂—Ph—CH₂ Ph Me 5-H₂NSO₂ 170.0-171.0 (standing*⁴) 177 174-Cl—Ph—(CH₂)₂ Ph Me 5-H₂NSO₂ oil*⁶ 178 17 2-MeO—Ph—(CH₂₎ ₂ Ph Me5-H₂NSO₂ oil*⁶ 179 2 2-i-PrO—Ph—CH₂ 3-F—Ph Et 4-Cl oil*⁶ 180 22-i-PrO—Ph—CH₂ 4-F—Ph Et 4-Cl oil*⁶ 181 2 2-i-PrO—Ph—CH₂ 4-Me—Ph Et 4-Cl79.5-80.5 (standing*⁴) 182 2 2-i-PrO—Ph—CH₂ 4-MeO—Ph Et 4-Cl 86.0-87.0(Et₂O-Hex) 183 2 2,5-(MeO)₂—Ph—CH₂ 3-F—Ph Et 4-Cl oil*⁶ 184 22,5-(MeO)₂—Ph—CH₂ 4-F—Ph Et 4-Cl oil*⁶ 185 2 2,5-(MeO)₂—Ph—CH₂ 4-Me—PhEt 4-Cl 101.0-101.5 (Et₂O-Hex) 186 2 2,5-(MeO)₂—Ph—CH₂ 4-MeO—Ph Et 4-Cloil*⁶ 187 2 2-i-PrO—Ph—CH₂ 3-F—Ph Et 5-Me oil*⁶ 188 2 2-i-PrO—Ph—CH₂4-Me—Ph Et 5-Me 70.0-71.0 (Et₂O-Hex) 189 2 2-i-PrO—Ph—CH₂ 4-MeO—Ph Et5-Me oil*⁶ 190 2 2,5-(MeO)₂—Ph—CH₂ 3-F—Ph Et 5-Me 67.0-68.0 (Et₂O-Hex)191 2 2,5-(MeO)₂—Ph—CH₂ 4-Me—Ph Et 5-Me 72.0-73.0 (Et₂O-Hex) 192 52-i-PrO—Ph—CH₂ 4-F—Ph NHMe 4-Cl 98.0-99.0 (Et₂O-Hex) 193 52-i-PrO—Ph—CH₂ 3-F—Ph NHMe 4-Cl oil*⁶ 194 5 2-i-PrO—Ph—CH₂ 4-Me—Ph NHMe4-Cl oil*⁶ 195 5 2-i-PrO—Ph—CH₂ 4-MeO—Ph NHMe 4-Cl oil*⁶ 196 52-i-PrO—Ph—CH₂ 4-Me—Ph NHMe 5-Me 79.0-80.0 (Et₂O-Hex) 197 52-i-PrO—Ph—CH₂ 4-MeO—Ph NHMe 5-Me oil*⁶ 198 5 2,5-(MeO)₂—Ph—CH₂ 4-Me—PhNHMe 5-Me 84.0-86.0 (Et₂O-Hex) *¹Compound Number *²Example Number usedfor synthesis of the corresponding compound. *³RecrystallizationSolvent: Hex = hexane, Et₂O = diethyl ether, IPE = diisopropyl ether,AcoEt = ethyl acetate, Hep = heptane. *⁴Crystallization by Purificationby silica gel column chromatography, drying and standing at roomtemperature. *⁵Crystallization from the solvent described. *⁶NMR and MSdata of oily substances are shown in Table 2 *⁷Monohydrochloride Symbolsin the table are as follows: Me: methyl, Et: ethyl, Pr; propyl, Bu:butyl, Pen: pentyl, Ph: phenylene, Py: pyridyl, Naph: naphthyl.

TABLE 2 001*¹: NMR(CDCl₃) δ(ppm); 1.92(3H, s), 3.73(3H, s), 4.51(1H, d,J=14.8Hz), 5.07(1H, d, J=14.8Hz), 6.70˜7.37(13H, m) EIMS m/e; 347(M⁺),121(M⁺−226, 100%) 003*¹: NMR(CDCl₃) δ(ppm); 1.18(3H, t, J=7.5Hz),1.94(3H, s), 3.66˜3.93(2H, m), 4.72(1H, d, J=14.5Hz), 5.17(1H, d,J=14.5Hz), 6.68˜7.40(13H, m) FABMS m/e; 362(M⁺+1), 135(M⁺−226, 100%)005*¹: NMR(CDCl₃) δ(ppm); 0.91(3H, t, J=7.3Hz), 1.53˜1.71(2H, m),1.93(3H, s), 3.60˜3.81(2H, m), 4.73(1H, d, J=14.5Hz), 5.18(1H, d,J=14.5Hz), 6.69˜7.37(13H, m) FABMS m/e; 376(M⁺+1), 149(M⁺−226, 100%)007*¹: NMR(CDCl₃) δ(ppm); 1.09(3H, d, J=7.0Hz), 1.17(3H, d, J=7.0Hz),1.93(3H, s), 4.26˜4.45(1H, m), 4.69(1H, d, J=14.5Hz), 5.17(1H, d, J=14.5Hz), 6.71˜7.40(13H, m) FABMS m/e; 376(M⁺+1), 149(M⁺−226, 100%)009*¹: NMR(CDCl₃) δ(ppm); 0.91(3H, d, J=6.8Hz), 0.93(3H, d, J=6.8Hz),1.79˜ 1.98(1H, m), 1.96(3H, s), 3.45˜3.60(2H, m), 4.72(1H, d, J=14.7Hz),5.19(1H, d, J=14.7Hz), 6.69˜7.36(13H, m) EIMS m/e; 389(M⁺), 163(M⁺−226,100%) 010*¹: NMR(CDCl₃) δ(ppm); 0.84˜0.96(3H, m), 1.23˜1.38(4H, m),1.50˜ 1.66(2H, m), 1.95(3H, s), 3.64˜3.84(2H, m), 4.70(1H, d, J=14.6Hz),5.17(1H, d, J=14.6Hz), 6.70˜7.40(13H, m) EIMS m/e; 403(M⁺), 107(M⁺−296,100%) 011*¹: NMR(CDCl₃) δ(ppm); 0.87(3H, d, J=6.6Hz), 0.88(3H, d,J=6.6Hz), 1.41˜ 1.51(2H, m), 1.58˜1.78(1H, m), 1.95(3H, s),3.67˜3.88(2H, m), 4.69(1H, d, J=14.7Hz), 5.17(1H, d, J=14.7Hz),6.71˜7.41(13H, m) EIMS m/e; 403(M⁺), 107(M⁺−296, 100%) 013*¹: NMR(CDCl₃)δ(ppm); 1.97(3Hx2/3, s), 2.13(3Hx1/3, s), 3.98(3H, s), 6.80˜7.62(13H, m)EIMS m/e; 333(M⁺), 291(M⁺−42, 100%) 015*¹: NMR(CDCl₃) δ(ppm); 1.96(3H,s), 3.53(3H, s), 3.81(3H, s), 4.70(1H, d, J=14.5Hz), 5.27(1H, d,J=14.5Hz), 6.73˜7.39(12H, m) FABMS m/e; 378(M⁺+1), 151(M⁺−226, 100%)016*¹: NMR(CDCl₃) δ(ppm); 1.92(3H, s), 3.52(3H, s), 3.76(3H, s),4.65(1H, d, J=14.4Hz), 5.09(1H, d, J=14.4Hz), 6.28(1H, d, J=2.4Hz),6.35(1H, dd, J=8.4, 2.4Hz), 6.83˜7.36(10H, m) EIMS m/e; 377(M⁺),151(M⁺−226 100%) 017*¹: NMR(CDCl₃) δ(ppm); 1.96(5H, s), 3.52(3H, s),3.66(3H, s), 4.70(1H, d, J=15.0Hz), 5.15(1H, d, J=15.0Hz),6.63˜7.38(12H, m) FABMS m/e; 378(M⁺+1), 151(M⁺−226, 100%) 018*¹:NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.23(3H, s), 3.54(3H, s), 3.66(3H, s),4.65(1H, d, J=14.5Hz), 5.13(1H, d, J=14.5Hz), 6.62˜7.40(11H, m) SIMSm/e; 392(M⁺+1), 151(M⁺−240, 100%) 020*¹: NMR(CDCl₃) δ(ppm); 1.96(3H, s),3.55(3H, s), 3.66(3H, s), 4.70(1H, d, J=15.0Hz), 5.13(1H, d, J=15.0Hz),6.49(1H, dd, J=9.9, 3.3Hz), 6.55˜ 7.44(10H, m) SIMS m/e; 396(M⁺+1),151(M⁺−244, 100%) 024*¹: NMR(CDCl₃) δ(ppm); 1.90(3H, s), 3.56(6H, s),4.91(1H, d, J=13.2Hz), 5.27(1H, d, J=13.2Hz), 6.34˜6.43(2H, m),6.71˜7.35(10H, m) EIMS m/e; 377(M⁺), 151(M⁺−226, 100%) 025*¹: NMR(CDCl₃)δ(ppm); 1.96(3H, s), 3.67(6H, s), 4.52(1H, d, J=14.5Hz), 5.08(1H, d,J=14.5Hz), 6.26˜6.39(3H, m), 6.82˜7.37(9H, m) EIMS m/e; 377(M⁺),151(M⁺−226, 100%) 028*¹: NMR(CDCl₃) δ(ppm); 1.89(3H, s), 2.10(3H, s),4.38(1H, d, J=14.0Hz), 5.38(1H, d, J=14.0Hz), 6.86˜7.20(13H, m) EIMSm/e; 375(M⁺), 185(M⁺−190, 100%) 029*¹: NMR(CDCl₃) δ(ppm); 1.97(3H, s),4.81(1H, d, J=15.0Hz), 5.29(1H, d, J=15.0Hz), 6.84˜7.53(13H, m) EIMSm/e; 353(M⁺+2), 351(M⁺), 316(M⁺−35, 100%) 030*¹: NMR(CDCl₃) δ(ppm);1.96(3H, s), 4.63(1H, d, J=15.0Hz), 5.04(1H, d, J=15.0Hz),6.83˜7.39(13H, m) EIMS m/e; 353(M⁺+2), 351(M⁺), 258(M⁺−93, 100%) 034*¹:NMR(CDCl₃) δ(ppm); 1.98(3H, s), 2.31(3H, s), 4.75(1H,d, J=14.8Hz),5.37(1H, d, J=14.8Hz), 6.83˜7.38(13H, m) EIMS m/e; 363(M⁺), 316(M⁺−47,100%) 037*¹: NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.26(6H, s), 2.44˜2.58(2H,m), 3.74˜ 3.97(2H, m), 4.72(1H, d, J=14.7Hz), 5.17(1H, d, J=14.7Hz),6.71˜ 7.38(13H, m) FABMS m/e; 405(M⁺+1, 100%) 038*¹: NMR(CDCl₃) δ(ppm);1.34(3Hx1/2, d, J=6.2Hz), 1.40(3Hx1/2, d, J= 6.2Hz), 1.93(3Hx1/2, s),1.97(3Hx1/2, s), 4.87(1Hx1/2, d, J=13.0Hz), 4.96(1Hx1/2, d, J=13.0Hz),5.10(1Hx1/2, d, J=13.0Hz), 5.19(1Hx1/2, d, J=13.0Hz), 6.60˜7.51(13H, m)EIMS m/e; 361(M⁺), 117(M⁺−244, 100%) 039*¹: NMR(CDCl₃) δ(ppm);0.88(3Hx1/2, t, J=7.2Hz), 0.91(3Hx1/2, t, J= 7.2Hz), 1.40˜1.85(2H, m),1.93(3Hx1/2, s), 1.96(3Hx1/2, s), 4.60˜ 5.40(3H, m), 6.64˜7.42(13H, m)EIMS m/e; 375(M⁺), 228(M⁺−147, 100%) 041*¹: NMR(CDCl₃) δ(ppm); 1.27(3H,t, J=7.3Hz), 1.98(3H, s), 4.18(2H, q, J= 7.3Hz), 5.20(1H, d, J=15.5Hz),5.55(1H, d, J=15.5Hz), 6.80˜7.44(11H, m), 7.59˜7.68(1H, m),7.74˜7.83(1H, m) EIMS m/e; 389(M⁺), 346(M⁺−43, 100%) 042*¹: NMR(CDCl₃)δ(ppm); 1.99(3H, s), 4.93(1H, d, J=15.4Hz), 5.29(1H, d, J=15.4Hz),6.92˜7.47(11H, m), 7.56˜7.60(1H, m), 7.82˜7.87(1H, m) FABMS m/e;362(M⁺+1, 100%) 043*¹: NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.84(3H, d,J=4.5Hz), 4.84(1H, d, J=15.0Hz), 5.13(1H, d, J=15.0Hz), 6.60˜6.78(1H,m), 6.82˜7.53(13H, m) EIMS m/e; 374(M⁺), 300(M⁺−74, 100%) 044*¹:NMR(CDCl₃) δ(ppm); 1.96(3H, s), 2.62(3H, s), 3.01(3H, s), 4.57(1H, d,J=15.0Hz), 5.26(1H, d, J=15.0Hz), 6.79˜7.48(13H, m) EIMS m/e; 388(M⁺),300(M⁺−88, 100%) 045*¹: NMR(CDCl₃) δ(ppm); 1.94(3H, s), 3.90˜4.14(4H,m), 4.61(1H, d, J= 14.7Hz), 5.55(1H, d, J=14.7Hz), 5.87(1H, s),6.91˜6.99(5H, m), 7.08˜ 7.40(7H, m), 7.50˜7.62(1H, m) FABMS m/e;390(M⁺+1), 286(M⁺−103, 100%) 048*¹: NMR(CDCl₃) δ(ppm); 1.02(3H, t,J=7.2Hz), 1.97(3H, s), 2.56˜2.72(2H, m), 5.07(1H, d, J=15.6Hz), 5.35(1H,d, J=15.6Hz), 6.85˜7.75(13H, m) EIMS m/e; 373(M⁺), 330(M⁺−43, 100%)050*¹: NMR(CDCl₃) δ(ppm); 0.89(3H, t, J=7.3Hz), 1.37˜1.55(2H, m),1.96(3H, s), 2.42˜2.51(2H, m), 4.68(1H, d, J=14.5Hz), 5.20(1H, d,J=14.5Hz), 6.81˜7.37(13H, m) SIMS m/e; 360(M⁺+1, 100%) 051*¹: NMR(CDCl₃)δ(ppm); 1.93(3H, s), 4.67(1H, d, J=14.5Hz), 5.22(1H, dd, J=10.8, 1.5Hz),5.35(1H, d, J=14.5Hz), 5.51(1H, dd, J=17.4, 1.5Hz), 6.80˜7.44(14H, m)EIMS m/e; 343(M⁺), 117(M⁺−226, 100%) 055*¹: NMR(CDCl₃) δ(ppm); 1.92(3H,s), 2.89(6H, s), 4.44(1H, d, J=14.3Hz), 5.09(1H, d, J=14.3Hz),6.53˜6.60(2H, m), 6.80˜7.34(11H, m) EIMS m/e; 360(M⁺), 134(M⁺−226, 100%)064*¹: NMR(CDCl₃) δ(ppm); 1.08(3H, t, J=6.5Hz), 2.16(2H, q, J=6.5Hz),3.56(3H, s), 4.69(1H, d, J=14.5Hz), 5.22(1H, d, J=14.5Hz), 6.70˜7.40(13H, m) EIMS m/e; 361(M⁺), 121(M⁺−240, 100%) 065*¹: NMR(CDCl₃)δ(ppm); 1.10(3H, t, J=7.5Hz), 2.16(2H, q, J=7.5Hz), 3.59(3H, s),4.69(1H, d, J=14.4Hz), 5.19(1H, d, J=14.4Hz), 6.70˜ 7.45(12H, m) EIMSm/e; 397(M⁺+2), 395(M⁺), 121(M⁺−274, 100%) 068*¹: NMR(CDCl₃) δ(ppm);1.05˜1.38(9H, m), 2.15(2H, q, J=7.4Hz), 4.27˜ 4.88(1H, m), 4.69(1H, d,J=14.4Hz), 5.18(1H, d, J=14.4Hz), 6.66˜ 7.42(12H, m) EIMS m/e;425(M⁺+2), 423(M⁺), 149(M⁺−274, 100%) 069*¹: NMR(CDCl₃) δ(ppm); 1.10(3H,t, J=7.5Hz), 2.16(2H, q, J=7.5Hz), 3.54(3H, s), 3.68(3H, s), 4.67(1H, d,J=14.5Hz), 5.17(1H, d, J=14.5Hz), 6.65˜7.43(11H, m) EIMS m/e; 427(M⁺+2),425(M⁺), 151(M⁺−274, 100%) 079*¹: NMR(CDCl₃) δ(ppm); 1.09(3H, t,J=7.5Hz), 2.20(2H, q, J=7.5Hz), 3.69(3H, s), 5.18(1H, d, J=15.5Hz),5.55(1H, d, J=15.5Hz), 6.80˜ 7.44(11H, m), 7.59˜7.68(1H, m),7.74˜7.83(1H, m) EIMS m/e; 389(M⁺), 332(M⁺−57, 100%) 071*¹: NMR(CDCl₃)δ(ppm); 0.86(3H, t, J=7.4Hz), 1.55˜1.73(2H, m), 2.12(2H, t, J=7.3Hz),3.57(3H, s), 4.67(1H, d, J=14.6Hz), 5.23(1H, d, J=14.6Hz),6.71˜7.38(13H, m) EIMS m/e; 375(M⁺), 121(M⁺−254, 100%) 073*¹: NMR(CDCl₃)δ(ppm); 0.83(3H, t, J=7.3Hz), 1.17˜1.35(2H, m), 1.52˜ 1.69(2H, m),2.14(2H, t, J=7.5Hz), 3.57(3H, s), 4.66(1H, d, J=14.5Hz), 5.23(1H, d,J=14.5Hz), 6.71˜7.38(13H, m) EIMS m/e; 389(M⁺), 121(M⁺−268, 100%) 074*¹:NMR(CDCl₃) δ(ppm); 0.88(6H, d, J=6.6Hz), 2.03(2H, d, J=6.6Hz),2.09˜2.16(1H, m), 3.58(3H, s), 4.65(1H, d, J=14.5Hz), 5.26(1H, d, J=14.5Hz), 6.71˜7.38(13H, m) EIMS m/e; 389(M⁺), 121(M⁺−268, 100%) 075*¹:NMR(CDCl₃) δ(ppm); 0.81˜0.87(3H, m), 1.12˜1.30(4H, m), 1.51˜ 1.69(2H,m), 2.13(2H, t, J=7.5Hz), 3.57(3H, s), 4.66(1H, d, J=14.7Hz), 5.23(1H,d, J=14.7Hz), 6.71˜7.37(13H, m) EIMS m/e; 403(M⁺), 121(M⁺−282, 100%)080*¹: NMR(CDCl₃) δ(ppm); 3.61(3H, s), 4.66(1H, d, J=14.1Hz), 5.40(1H,d, J=14.1Hz), 6.72˜7.44(13H, m) EIMS m/e; 401(M⁺), 121(M⁺−280, 100%)082*¹: NMR(CDCl₃) δ(ppm); 2.15(3H, s), 3.58(3H, s), 4.46(1H, d,J=14.8Hz), 4.59(1H, d, J=14.8Hz), 4.74(1H, d, J=14.5Hz), 5.16(1H, d,J=14.5Hz), 6.71˜7.38(13H, m) EIMS m/e; 405(M⁺), 121(M⁺−284, 100%) 083*¹:NMR(CDCl₃) δ(ppm); 3.56(3H, s), 3.64(1H, d, J=15.9Hz), 3.76(1H, d,J=15.9Hz), 4.78(1H, d, J=14.2Hz), 5.18(1H, d, J=14.2Hz), 6.71˜ 7.40(13H,m) EIMS m/e; 388(M⁺), 121(M⁺−267, 100%) 087*¹: NMR(CDCl₃) δ(ppm);3.62(3Hx3/4, s), 3.78(3Hx1/4, s), 4.75(2Hx1/4, s), 4.99(2Hx3/4, s),6.72˜7.40(13H, m), 8.35(1Hx3/4, s), 8.47(1Hx1/4, s) CIMS m/e; 334(M⁺+1),121(M⁺−212, 100%) 088*¹: NMR(CDCl₃) δ(ppm); 1.23(3Hx3/4, t, J=6.9Hz),1.40(3Hx1/4, t, J= 6.9Hz), 3.84(2Hx3/4, q, J=6.9Hz), 3.98(2Hx1/4, q,J=6.9Hz), 4.75(2Hx1/4, s), 5.00(2Hx3/4, s), 6.70˜7.43(13H, m),8.34(1Hx3/4, s), 8.48(1Hx1/4, s) CIMS m/e; 348(M⁺+1), 135(M⁺−212, 100%)098*¹: NMR(CDCl₃) δ(ppm); 3.58(3H, s), 3.63(3H, s), 4.82(2H, br s),6.75˜7.42(13H, m) EIMS m/e; 363(M⁺), 121(M⁺−242, 100%) 099*¹: NMR(CDCl₃)δ(ppm); 1.06˜1.25(3H, m), 3.63(3H, s), 3.98˜4.15(2H, m), 4.82(2H, br s),6.75˜7.41(13H, m) EIMS m/e; 377(M⁺), 121(M⁺−256, 100%) 100*¹: NMR(CDCl₃)δ(ppm); 2.00(3H, s), 2.22(3H, s), 3.58(3H, s), 4.73(1H, d, J=14.6Hz),5.28(1H, d, J=14.6Hz), 6.64(1H, dd, J=8.2, 1.2Hz), 6.65˜7.34(10H, m),7.38(1H, dd, J=7.5, 1.8Hz) EIMS m/e; 361(M⁺), 121(M⁺−240, 100%) 101*¹:NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.33(3H, s), 3.58(3H, s), 4.71(1H, d,J=14.6Hz), 5.16(1H, d, J=14.6Hz), 6.70˜7.30(11H, m), 7.35(1H, dd, J=7.5,1.5Hz) EIMS m/e; 361(M⁺), 121(M⁺−240, 100%) 103*¹: NMR(CDCl₃) δ(ppm);2.02(3H, s), 3.61(3H, s), 3.75(3H, s), 4.74(1H, d, J=14.7Hz), 5.26(1H,d, 14.7Hz), 6.57(1H, dd, J=8.3, 1.2Hz), 6.76(1H, d, J=8.3Hz),6.78˜7.26(9H, m), 7.39(1H, dd, J=7.5, 1.8Hz) EIMS m/e; 377(M⁺),121(M⁺−256, 100%) 104*¹: NMR(CDCl₃) δ(ppm); 1.94(3H, s), 3.57(3H, s),3.79(3H, s), 4.69(1H, d, J=14.6Hz), 5.17(1H, d, J=14.6Hz), 6.43˜6.55(2H,m), 6.62˜7.05(6H, m), 7.10˜7.29(3H, m), 7.35(1H, dd, J=7.5, 1.8Hz) EIMSm/e; 377(M⁺), 121(M⁺−256, 100%) 105 NMR(CDCl₃) δ(ppm); 1.96(3H, s),3.58(3H, s), 3.81(3H, s), 4.77(1H, d, J=14.6Hz), 5.16(1H, d, J=14.6Hz),6.70˜6.74(2H, m), 6.79˜7.25(9H, m), 7.36(1H, dd, J=7.5, 1.8Hz) EIMS m/e;377(M⁺), 121(M⁺−256, 100%) 109*¹: NMR(CDCl₃) δ(ppm); 1.94(3H, s),3.56(3H, s), 4.75(1H, d, J=14.6Hz), 5.12(1H, d, J=14.6Hz),6.67˜7.25(11H, m), 7.34(1H, dd, J=7.5, 1.8Hz) EIMS m/e; 365(M⁺),121(M⁺−244, 100%) 118*¹: NMR(CDCl₃) δ(ppm); 1.96(3H, s), 3.52(3H, s),4.96(1H, d, J=14.5Hz), 5.02(1H, d, J=14.5Hz), 6.50˜7.42(12H, m) FABMSm/e; 366(M⁺+1), 121(M⁺−244, 100%) 127*¹: NMR(CDCl₃) δ(ppm); 1.97(3H, s),3.64(3H, s), 4.70(1H, d, J=14.5Hz), 5.16(1H, d, J=14.5Hz), 6.47˜6.60(2H,m), 6.73˜7.38(15H, m) FABMS m/e; 440(M⁺+1), 121(M⁺−318, 100%) 150*¹NMR(CDCl₃) δ(ppm); 2.00(3H, s), 2.25(6H, s), 3.43(1H, d, J=115Hz),3.52(1H, d, J=11.5Hz), 3.59(3H, s), 4.68(1H, d, J=14.7Hz), 5.30(1H, d,J=14.7Hz), 6.64˜7.56(12H, m). FABMS m/e; 405(M⁺+1, 100%) 151*¹:NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.24(6H, s), 3.40(2H, s), 3.59(3H, s)4.68(1H, d, J=14.6Hz), 5.19(1H, d, J=14.6Hz), 6.70˜7.40(12H, m) FABMSm/e; 405(M⁺+1, 100%) 152*¹: NMR(CDCl₃) δ(ppm); 1.95(3H, s), 2.25(6H, s),3.40(2H, s), 3.59(3H, s) 4.68(1H, d, J=14.5Hz), 5.19(1H, d, J=14.5Hz),6.68˜7.40(12H, m) EIMS m/e; 404(M⁺), 317(M⁺−87, 100%) 160*¹: NMR(CDCl₃)δ(ppm); 1.95(3H, s), 3.53(3H, s), 3.65(3H, s), 4.77(1H, d, J=14.7Hz),5.04(1H, d, J=14.7Hz), 6.60˜7.63(11H, m) EIMS m/e; 420(M⁺), 151(M⁺−269,100%) 167*¹: NMR(CDCl₃) δ(ppm); 1.12(3H, d, J=6.2Hz), 1.17(3H, d,J=6.2Hz), 1.92(3H, s), 4.37(1H, sept, J=6.2Hz), 4.73(1H, d, J=14.3Hz),5.07(1H, d, J=14.3Hz), 6.52(1H, ddd, J=9.7, 2.4, 2.4Hz), 6.62˜7.39(10H,m) FABMS m/e; 428(M⁺+1), 149(M⁺−278, 100%) 168*¹: NMR(CDCl₃) δ(ppm);1.11(3H, d, J=6.0Hz), 1.14(3H, d, J=6.0Hz), 1.93(3H, s) 2.25(3H, s),4.35(1H, sept, J=6.0Hz), 4.68(1H, d, J=14.5Hz), 5.03(1H, d, J=14.5Hz),6.42˜6.53(1H, m), 6.60˜7.40(10H, m) FABMS m/e; 408(M⁺+1), 149(M⁺−258,100%) 169*¹: NMR(CDCl₃) δ(ppm); 1.11(3H,d, J=6.0Hz), 1.14(3H, d,J=6.0Hz), 1.94(3H, s) 2.22(3H, s), 4.36(1H, sept, J=6.0Hz), 4.73(1H, d,J=14.6Hz), 5.04(1H, d, J=14.6Hz), 6.65˜7.20(10H, m), 7.36(1H, dd, J=7.5,1.8Hz) FABMS m/e; 408(M⁺+1), 149(M⁺−258, 100%) 170*¹: NMR(CDCl₃) δ(ppm);1.11(3H, d, J=6.0Hz), 1.16(3H, d, J=6.0Hz), 1.95(3H, s) 2.20(3H, s),2.32(3H, s), 4.37(1H, sept, J=6.0Hz), 4.67(1H, d, J=14.7Hz), 5.10(1H, d,J=14.7Hz), 6.68˜7.20(10H, m), 7.38(1H, dd, J= 7.5, 1.5Hz) FABMS m/e;404(M⁺+1), 149(M⁺−254, 100%) 171*¹: NMR(CDCl₃) δ(ppm); 1.95(3H, s),2.24(3H, s), 3.53(3H, s), 3.67(3H, s), 4.72(1H, d, J=14.7Hz), 5.04(1H,d, J=14.7Hz), 6.62˜7.06(10H, m) FABMS m/e; 410(M⁺+1), 151(M⁺−258, 100%)177*¹: NMR(CDCl₃) δ(ppm); 1.92(3H, s), 2.74˜3.12(2H, m), 3.58˜3.77(1H,m), 4.05˜4.21(1H, m), 4.85˜5.12(2H, m), 6.93(1H, d, J=6.9Hz),6.97˜7.53(10H, m), 7.79(1H, dd, J=8.8, 2.4Hz) FABMS m/e; 445(M⁺+1, 100%)178*¹: NMR(CDCl₃) δ(ppm); 1.93(3H, s), 2.78˜3.13(2H, m), 3.60˜3.92(1H,m), 3.73(3H, s), 4.04˜4.23(1H, m), 4.72˜5.02(2H, m), 6.77˜7.50(11H, m),7.75(1H, dd, J=8.8, 2.4Hz) FABMS m/e; 441(M⁺+1, 100%) 179*¹: NMR(CDCl₃)δ(ppm); 1.02˜1.23(9H, m), 2.12(2H, q, J=7.3Hz), 4.37(1H, sept, J=6.0Hz),4.70(1H, d, J=14.3Hz), 5.11(1H, d, J=14.3Hz), 6.53(1H, ddd, J=9.7, 2.3,2.3Hz), 6.63˜7.39(10H, m) FABMS m/e; 442(M⁺+1), 154(M⁺−287, 100%) 180*¹:NMR(CDCl₃) δ(ppm); 1.00˜1.22(9H, m), 2.14(2H, t, J=7.5Hz), 4.38(1H,sept, J=6.0Hz), 4.75(1H, d, J=14.3Hz), 5.12(1H, d, J=14.3Hz),6.63˜7.23(10H, m), 7.36(1H, dd, J=7.5, 1.5Hz), FABMS m/e; 442(M⁺+1),154(M⁺−287, 100%) 183*¹: NMR(CDCl₃) δ(ppm); 1.10(3H, t, J=7.4Hz),2.13(2H, q, J=7.4Hz), 3.53(3H, s), 3.68(3H, s), 4.68(1H, d, J=14.4Hz),5.11(1H, d, J=14.4Hz), 6.51˜7.06(9H, m), 7.22˜7.40(1H, m) FABMS m/e;444(M⁺+1), 154(M⁺−289, 100%) 184*¹: NMR(CDCl₃) δ(ppm); 1.11(3H, t,J=7.5Hz), 2.15(2H, q, J=7.5Hz), 3.53(3H, s), 3.68(3H, s), 4.71(1H, d,J=14.5Hz), 5.13(1H, d, J=14.5Hz), 6.63˜7.14(10H, m) FABMS m/e;444(M⁺+1), 151(M⁺−292, 100%) 186*¹: NMR(CDCl₃) δ(ppm); 1.12(3H, t,J=7.5Hz), 2.17(3H, q, J=7.5Hz), 3.54(3H, s), 3.69(3H, s), 3.83(3H, s),4.72(1H, d, J=14.5Hz), 5.16(1H, d, J=14.5Hz), 6.65˜7.00(10H, m) FABMSm/e; 456(M⁺+1), 154(M⁺−301, 100%) 187*¹: NMR(CDCl₃) δ(ppm);1.00˜1.24(9H, m), 2.13(2H, q, J=7.5Hz), 2.24(3H, s), 4.35(1H, sept,J=5.9Hz), 4.65(1H, d, J=14.5Hz), 5.07(1H, d, J= 14.7Hz), 6.48(1H, ddd,J=10.2, 2.4, 2.4Hz), 6.58˜6.90(6H, m), 6.95˜ 7.40(4H, m) FABMS m/e;422(M⁺+1), 149(M⁺−272, 100%) 189*¹: NMR(CDCl₃) δ(ppm); 1.02˜1.25(9H, m),2.17(2H, q, J=7.5Hz), 2.19(3H, s), 3.80(3H, s), 4.36(1H, sept, J=6.0Hz),4.71(1H, d, J=14.6Hz), 5.12(1H, d, J=14.6Hz), 6.64(1H, d, J=8.4Hz),6.62˜6.99(8H, m), 7.07˜7.20(1H, m), 7.41(1H, dd, J=7.6, 1.7Hz) FABMSm/e; 434(M⁺+1), 107(M⁺−326, 100%) 193*¹: NMR(CDCl₃) δ(ppm); 1.18(6H, d,J=5.9Hz), 2.75(3H, d, J=4.6Hz), 4.44(1H, sept, J=5.9Hz), 4.46(1H, br s),4.80(2H, s), 6.55˜7.40(11H, m) FABMS m/e; 443(M⁺+1), 149(M⁺−293, 100%)194*¹: NMR(CDCl₃) δ(ppm); 1.18(6H, d, J=6.1Hz), 2.35(3H, s), 2.77(3H, d,J= 4.8Hz), 4.42(1H, sept, J=6.1Hz), 4.43(1H, br 5), 4.86(2H, s), 6.72˜7.22(10H, m), 7.42(1H, dd, J=7.5, 1.8Hz) FABMS m/e; 439(M⁺+1),154(M⁺−284, 100%) 195*¹: NMR(CDCl₃) δ(ppm); 1.18(6H, d, J=6.2Hz),2.79(3H, d, J=4.6Hz), 3.82(3H, s), 4.43(1H, sept, J=6.2Hz), 4.44(1H, brs), 4.87(2H, s), 6.72(1H, d, J=2.2Hz), 6.73˜6.96(7H, m), 7.00(1H, d,J=8.4Hz), 7.12˜ 7.23(1H, m), 7.42(1H, dd, J=7.5, 1.8Hz) FABMS m/e;455(M⁺+1), 107(M⁺−347, 100%) 197*¹: NMR(CDCl₃) δ(ppm); 1.16(6H, d,J=5.9Hz), 2.22(3H, s), 2.76(3H, d, J=4.6Hz), 3.81(3H, s), 4.41(1H, sept,J=5.9Hz), 4.43(1H, br s), 4.77˜ 4.90(2H, m), 6.63˜7.22(10H, m),7.44˜7.53(1H, m) FABMS m/e; 435(M⁺+1), 107(M⁺−327, 100%) *¹: CompoundNumber (See Table 1)

Experiment [MDR Receptor Binding Assay]

Crude mitochondria fractions prepared from rat cerebral cortex were usedas a receptor sample, and [³H]PK11195 was used as a [³H]-labeled ligand.

A binding assay using the [³H]-labeled ligand was carried out accordingto the following method as described in Journal of Pharmacology andExperimental Therapeutics, 262, 971(1992).

Preparation of Receptor Sample: Rat cerebral cortex was homogenizedusing a Teflon-coated homogenizer in a 10 mM HEPES buffer (pH 7.4)containing 0.32 M sucrose in ten volumes of the wet weight. Thehomogenate was centrifuged at 900×g for 10 minutes, and the resultingsupernatant was centrifuged at 9,000×g for 10 minutes. The precipitatewas suspended in a HEPES buffer to give a protein concentration of 1mg/ml, and centrifuged at 12,000×g for 10 minutes. The resultingprecipitate was suspended in a 50 mM HEPES buffer (pH 7.4) to give acrude mitochondria fraction.

MDR Binding Assay: Mitochondria sample (1.0 mg protein/ml), [³H]PK11195(2 nM) and the test drug were reacted at 4° C. for 90 minutes. Aftercompletion of the reaction, the reaction mixture was filtered withsuction through a glass filter (GF/B) treated with 0.3%polyethyleneimine, and the radioactivity on the filter was measured by aliquid scintillation spectrometer.

The binding at the reaction in the presence of 10 μM PK11195 was definedas non-specific binding of [3H]PK11195, and the difference between totalbinding and non-specific binding was defined as specific binding. Afixed concentration of [³H]PK11195 (2 nM) was reacted with variedconcentrations of the test drug under the above-mentioned conditions togive an inhibition curve, and the concentration (IC₅₀) of the test drugto exhibit 50% inhibition of [³H]PK11195 binding was measured by theinhibition curve, and results are shown in Table 3.

TABLE 3 MDR MDR MDR MDR Comp. No. IC₅₀ (nM) Comp. No. IC₅₀ (nM) Comp.No. IC₅₀ (nM) Comp. No. IC₅₀ (nM) 001 1.38 027 3.20 066 0.925 098 0.498002 0.658 028 3.20 067 1.08 099 0.870 003 0.123 029 0.486 071 1.26 1000.112 004 0.791 030 1.96 072 3.51 101 0.285 005 0.118 031 1.23 073 1.52102 0.123 006 0.677 032 6.73 075 1.83 103 0.722 007 0.0977 033 3.51 0760.955 104 0.343 008 0.870 034 0.179 077 5.59 105 0.163 009 0.112 0400.0643 079 4.64 108 0.413 010 0.149 046 0.376 080 4.64 109 0.285 0110.163 047 0.265 081 0.343 110 8.90 012 0.453 049 4.23 082 8.90 112 0.376013 9.77 050 0.215 085 3.85 116 0.343 014 2.21 051 0.196 087 0.572 1170.792 015 0.285 052 4.64 088 0.163 118 0.498 016 0.722 054 1.26 089 3.51120 0.196 017 0.0850 055 1.83 090 4.64 121 2.01 019 0.196 056 2.92 0911.83 123 0.870 021 0.310 060 0.955 092 0.722 124 0.343 022 0.179 0610.498 093 0.870 125 2.21 023 0.424 062 1.05 094 0.925 126 8.11 025 0.260064 0.0933 095 3.77 127 3.51

INDUSTRIAL APPLICABILITY

The present invention has provided drugs having a high affinity for MDR,and therefore they are useful as therapeutic or preventive drugs ofcentral diseases such as anxiety, related diseases thereto, depression,epilepsy, sleeping disorders, recognition and leaning disability orschizophrenia, dyskinesia accompanied by muscle rigidity, feedingdisorders, circulation disorders, drug dependence, cancer, lipidmetabolism abnormality, cerebral infarction, AIDS, Alzheimer's diseaseor Huntington chorea.

What is claimed is:
 1. An aryloxyaniline derivative represented by theformula:

wherein Ar¹ and Ar² are the same or different, and are each asubstituted or unsubstituted phenyl group, a substituted orunsubstituted pyridyl group or a naphthyl group, provided that Ar¹ andAr² are not both phenyl or both naphthyl and are not phenyl andnaphthyl, R¹ is a hydrogen atom, a substituted or unsubstituted alkylgroup having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbonatoms, a substituted or unsubstituted phenyl group or a group of theformula: —NR²(R³) (wherein R² and R³ are the same or different, and areeach a hydrogen atom or an alkyl group having 1 to 10 carbon atoms), X¹is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxygroup having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, atrifluoromethyl group, a carbamoyl group or an aminosulfonyl group, Y¹is a branched or unbranched alkylene group having 1 to 6 carbon atoms ora single bond; and pharmaceutically acceptable salts thereof, andwherein the substituted phenyl group is a phenyl group substituted withone to three members selected from the group consisting of: an alkylgroup having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbonatoms substituted with halogen atoms, hydroxyl groups, carboxyl groupsor alkoxycarbonyl groups, an alkenyl group having 2 to 10 carbon atoms,an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1to 10 carbon atoms, a group of the formula: —O—Z—R⁴ (wherein Z is abranched or unbranched alkylene group having 1 to 10 carbon atoms, andR⁴ is an amino group, an amino group substituted with one or two of analkyl group having 1 to 7 carbon atoms, a cyclic amino group having 2 to7 carbon atoms, a hydroxyl group, a carboxyl group or an alkoxycarbonylgroup), an alkanoyl group having 2 to 10 carbon atoms or a ketal formthereof, a formyl group or an acetal form thereof, a carboxyl group, analkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, acarbamoyl group substituted with one or two of an alkyl group having 1to 10 carbon atoms on the nitrogen atom, an aminosulfonyl group, anaminosulfonyl group substituted with one or two of an alkyl group having1 to 10 carbon atoms on the nitrogen atom, a halogen atom, and a nitrogroup, and wherein the substituted pyridyl group is a pyridyl groupsubstituted with one to three of an alkoxy group having 1 to 10 carbonatoms.
 2. A medicine comprising the aryloxyaniline derivative or thepharmaceutically acceptable salt thereof according to claim 1 and anadditive.
 3. A ligand for MDR comprising the aryloxyaniline derivativeor the pharmaceutically acceptable salt thereof according to claim 1 asan active ingredient and an additive.